Inhibitor of apoptosis protein (IAP) antagonists

ABSTRACT

Provided herein are compounds that modulate the activity of inhibitor of apoptosis proteins (IAPs), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

RELATED APPLICATIONS

This application is filed pursuant to 35 U.S.C. §371 as a U.S. NationalPhase Application of International Application No. PCT/US2013/072064entitled “INHIBITOR OF APOPTOSIS PROTEIN (IAP) ANTAGONISTS”, filed Nov.26, 2013, which application claims the benefit of U.S provisional patentapplication no. 61/731,794 entitled “INHIBITOR OF APOPTOSIS PROTEIN(IAP) ANTAGONISTS” filed on Nov. 30, 2012, each of which is incorporatedby reference in its entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with the support of the United States governmentunder Contract number HG005033 by the National Institutes of Health.

SUMMARY OF THE INVENTION

Described herein are compounds that modulate the activity of certainproteins involved in apoptotic pathways, or signaling pathwaysassociated with inflammation and/or autoimmune diseases and/or celldivision and/or angiogenesis. In some embodiments, the compoundsdescribed herein are antagonists of inhibitor of apoptosis proteins(IAPs). In some embodiments, the compounds described herein are pan-IAPantagonists. In some embodiments, the compounds described herein areuseful for the treatment of cancer, inflammatory diseases, and/orautoimmune diseases as described herein.

In one aspect, provided herein are compounds having the structure ofFormula A-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8c))(R^(8d)); provided that W¹ and        W² are not both O, or both S;    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl), or        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is O, N—R^(A), S, S(O), or S(O)₂, then X² is        C(R^(2a)R^(2b));    -   or:    -   X¹ is CR^(2c)R^(2d) and X² is CR^(2a)R^(2b), and R^(2c) and        R^(2a) together form a bond;    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring;    -   or:    -   X¹ is CH₂ and X² is C═O, C═C(R^(C))₂, or C═NR^(C); where each        R^(C) is independently selected from H, —CN, —OH, alkoxy,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2e), R^(2d), are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is NHC(═O)R⁷, —C(═O)NHR⁷, NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, (C₁-C₃alkyl)-NHC(═O)R⁷,        (C₁-C₃alkyl)-C(═O)NHR⁵, (C₁-C₃alkyl)-NHS(═O)₂R⁷,        (C₁-C₃alkyl)-S(═O)₂NHR⁷; (C₁-C₃alkyl)-NHC(═O)NHR⁷,        (C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), or -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) are independently selected        from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆ alkoxy,        C₁-C₆heteroalkyl, and substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl        or heteroaryl is substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In one aspect, provided herein are compounds having the structure ofFormula A-XXI, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W² is O, S, or C(R^(8e))(R^(8d));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a), and R^(2b) are independently selected from H,        substituted or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), C₁-C₆alkyl-(substituted or unsubstituted        aryl), —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl), or        —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   R^(8c) and R^(8d) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹;        and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In one aspect, provided herein are compounds having the structure ofFormula B-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkyl-(substituted or        unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        C₁-C₆alkyl-(substituted or unsubstituted aryl),        C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is selected from N—R^(A), then X² is C═O, or        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is selected from S, S(O) and S(O)₂, then X² is        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is O, then X² is selected from CR^(2c)R^(2d) and        N—R^(A), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ is CH₂, then X² is selected from O, N—R^(A), S, S(O),        and S(O)₂, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ is CR^(2e)R^(2f) and X² is CR^(2c)R^(2d), and R^(2e) and        R^(2c) together form a bond, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ and X³ are both CH₂ and X² is C═O, C═C(R^(C))₂, or C═NR^(C);        where each R^(C) is independently selected from H, —CN, —OH,        alkoxy, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), C₁-C₆alkyl-(substituted or unsubstituted        aryl), or C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X³ is        CR^(2a)R^(2b);    -   or:    -   X² and X³ are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X¹ is        CR^(2e)R^(2f);    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8e))(R^(8d)); provided that W¹ and        W² are not both O, or both S;    -   R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is NHC(═O)R⁷, —C(═O)NHR⁷, NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, (C₁-C₃alkyl)-NHC(═O)R⁷,        (C₁-C₃alkyl)-C(═O)NHR⁵, (C₁-C₃alkyl)-NHS(═O)₂R⁷,        (C₁-C₃alkyl)-S(═O)₂NHR⁷; (C₁-C₃alkyl)-NHC(═O)NHR⁷,        (C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), or -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) are independently selected        from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆ alkoxy,        C₁-C₆heteroalkyl, and substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8a) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In one aspect, provided herein are compounds having the structure ofFormula B-XXII, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W² is O, S, or C(R^(8e))(R^(8d));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a) and R^(2b) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, and C(═O)R^(D);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), C₁-C₆alkyl-(substituted or unsubstituted        aryl), C₁-C₆alkyl-(substituted or unsubstituted heteroaryl), or        NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), C₁-C₆alkyl-(substituted or unsubstituted        aryl), or C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   R^(8c) and R^(8d) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹;        and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In one aspect, provided herein are compounds having the structure ofFormula C-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkyl-(substituted or        unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is selected from N—R^(A), S, S(O) and S(O)₂, then X² is        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is O, then X² is selected from CR^(2c)R^(2d) and        N—R^(A), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ is CH₂, then X² is selected from O, N—R^(A), S, S(O),        and S(O)₂, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ is CR^(2e)R^(2f) and X² is CR^(2c)R^(2d), and R^(2e) and        R^(2c) together form a bond, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X³ is        CR^(2a)R^(2b);    -   or:    -   X² and X³ are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X¹ is        CR^(2e)R^(2f);    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8c))(R^(8d)); provided that W¹ and        W² are not both O, or both S;    -   R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), C₁-C₆alkyl-(substituted or unsubstituted        aryl), C₁-C₆alkyl-(substituted or unsubstituted heteroaryl) and        C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), C₁-C₆alkyl-(substituted or unsubstituted        aryl), —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl), or        —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) are independently selected        from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆ alkoxy,        C₁-C₆heteroalkyl, and substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8a)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8a) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In one aspect, provided herein are compounds having the structure ofFormula C-XXI, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W² is O, S, or C(R^(8c))(R^(8d));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a) and R^(2b) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   R^(8c) and R^(8d) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹;        and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In one aspect, provided herein are compounds having the structure ofFormula D-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is selected from N—R^(A), S, S(O) and S(O)₂, then X² is        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is O, then X² is selected from CR^(2c)R^(2d) and        N—R^(A), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ is CH₂, then X² is selected from O, N—R^(A), S, S(O),        and S(O)₂, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ is CR^(2e)R^(2f) and X² is CR^(2c)R^(2d), and R^(2e) and        R^(2c) together form a bond, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ and X³ are both CH₂ and X² is C═O, C═C(R^(C))₂, or C═NR^(C);        where each R^(C) is independently selected from H, —CN, —OH,        alkoxy, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X³ is        CR^(2a)R^(2b);    -   or:    -   X² and X³ are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X¹ is        CR^(2e)R^(2f);    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8c))(R^(8d));    -   W³ is O, S, N—R^(A), or C(R^(8e))(R^(8f)); provided that the        ring comprising W¹, W² and W³ does not comprise two adjacent        oxygen atoms or sulfur atoms;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   R^(2a), R^(2b), R^(2c), R^(2d) R^(2e), and R^(2f) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are        independently selected from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and substituted or unsubstituted        aryl;    -   or:    -   R^(8a), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8b) and R^(8c) together form a bond;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) are as defined above, and        R^(8c) and R^(8e) together form a bond;    -   or:    -   R^(8a), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8b) and R^(8c) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) are as defined above, and        R^(8c) and R^(8e) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8c), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8a) and R^(8b) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8e) and R^(8f) are as defined above, and        R^(8c) and R^(8d) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8c), and R^(8d) are as defined above, and        R^(8e) and R^(8f) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In one aspect, provided herein are compounds having the structure ofFormula D-XXII, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W³ is O, S, or C(R^(8e))(R^(8f));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a) and R^(2b) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl        and C₁-C₆fluoroalkyl;    -   R^(8e) and R^(8f) are independently selected from H, C₁-C₆alkyl        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹;        and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In another aspect, provided herein are compounds having the structure ofFormula E-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is selected from N—R^(A), S, S(O) and S(O)₂, then X² is        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is O, then X² is selected from CR^(2c)R^(2d) and        N—R^(A), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ is CH₂, then X² is selected from O, N—R^(A), S, S(O),        and S(O)₂, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ is CR^(2e)R^(2f) and X² is CR^(2c)R^(2d), and R^(2e) and        R^(2c) together form a bond, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X³ is        CR^(2a)R^(2b);    -   or:    -   X² and X³ are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X¹ is        CR^(2e)R^(2f);    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8c))(R^(8d));    -   W³ is O, S, N—R^(A), or C(R^(8e))(R^(8f)); provided that the        ring comprising W¹, W² and W³ does not comprise two adjacent        oxygen atoms or sulfur atoms;    -   R^(2a), R^(2b), R^(2c), R^(2d) R^(2e), and R^(2f) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are        independently selected from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and substituted or unsubstituted        aryl;    -   or:    -   R^(8a), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8b) and R^(8c) together form a bond;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) are as defined above, and        R^(8c) and R^(8e) together form a bond;    -   or:    -   R^(8a), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8b) and R^(8c) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) are as defined above, and        R^(8c) and R^(8e) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8c), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8a) and R^(8b) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8e) and R^(8f) are as defined above, and        R^(8c) and R^(8d) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8c), and R^(8d) are as defined above, and        R^(8e) and R^(8f) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁i-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In another aspect, provided herein are compounds having the structure ofFormula E-XXI, or pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W³ is O, S, or C(R^(8e))(R^(8f));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a) and R^(2b) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   R^(8e) and R^(8f) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl        or heteroaryl is substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In a further aspect, provided herein are compounds of Formula A, FormulaB, Formula C, Formula D, Formula E, Formula F, or Formula G, andcompositions comprising compounds of Formula A, Formula B, Formula C,Formula D, Formula E, Formula F, or Formula G, for treatment of cancer,inflammatory diseases and/or autoimmune diseases in an individual inneed thereof.

In a further aspect, provided herein are compounds of Formula A, FormulaB, Formula C, Formula D, Formula E, Formula F, or Formula G, andcompositions comprising compounds of Formula A, Formula B, Formula C,Formula D, Formula E, Formula F, or Formula G, for inhibition of theactivity of inhibitor of apoptosis proteins (IAPs) in an individual inneed thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 exemplifies the effects of compounds 16c, 17a, 17b, and 17c onMDA-MB-231 breast cancer cell survival.

DETAILED DESCRIPTION OF THE INVENTION

Aberrant and uncontrolled cell growth due to apoptosis suppression is ahallmark of cancer cells. Cancer cells often display aberrantupregulation of pathways which inhibit apoptosis, allowing the cancercells to proliferate. One such pathway which is upregulated in cancercells is the inhibitor of apoptosis (IAP) pathway. The members of theIAP family are functionally and structurally related proteins, whichinhibit apoptosis. IAPs share a Baculovirus IAP Repeat domain, eachhaving one to three copies. Eight members of the IAP family havecurrently been identified, in both baculovirus and humans. Five humanmembers of the IAP family include: XIAP, c-IAP1 (also, BIRC2), C-IAP2(also, BIRC3), NAIP, and survivin. In certain instances, XIAP inhibitsapoptosis by binding to and inhibiting the activity of caspase-9,caspase-3 and caspase 7.

Alterations in IAP proteins are found in many types of human cancer andare associated with chemoresistance, disease progression and poorprognosis. When the IAP pathway is upregulated, the IAP proteins bind toand prevent initiator and effector caspases from cleaving downstreamcellular proteins.

The proteolytic action of caspases is required to allow the cell deathcascade to progress normally. Accordingly, provided herein are compoundsthat bind the upregulated IAP proteins. The compounds provided herein,in some embodiments, bind to IAPs and prevent them from suppressingcaspase action, thereby allowing the cell death cascade to progressnormally. In other words, provided herein are compounds that inhibit theaction of IAP proteins, thereby inducing apoptosis in cells.

One protein implicated in binding with IAPs is SMAC. SMAC is amitochondrial protein that negatively regulates apoptosis or programmedcell death. When a cell is primed for apoptosis by the final executionstep of caspase activation, SMAC binds to IAP, which prevents IAP frombinding to, and deactivating caspases. Thus SMAC promotes apoptosis byactivating caspases.

In some embodiments, the compounds described herein are nonpeptidic SMACmimetics and induce apoptosis (e.g., in cancer cells). In someembodiments, the compounds described herein are IAP antagonists.

In certain instances, IAPs not only regulate caspases and apoptosis, butalso modulate inflammatory signalling and immunity, mitogenic kinasesignalling, proliferation and mitosis, as well as cell invasion andmetastasis. Inhibitor of apoptosis (IAP) proteins have emerged asregulators of innate immune signaling downstream of Pattern RecognitionReceptors (PRRs) such as Toll-like receptor 4 (TLR4), Nucleotide-BindingOligomerization Domain 1 (NOD1) and NOD2 receptors, and RetinoicAcid-Inducible Gene (RIG)-I Receptor. In certain instances, CellularInhibitor of Apoptosis Protein-1 (cIAP1; also Baculoviral IAP RepeatContaining 2 or BIRC2), Cellular Inhibitor of Apoptosis Protein-2(cIAP2; also, Baculoviral IAP Repeat Containing 3 or BIRC3), andX-linked Inhibitor of Apoptosis (XIAP) facilitate ubiquitin-dependentsignaling activated by these PRRs and mediate activation of nuclearfactor-kappa B (NF-κB) transcription factors as well as the MAP kinasesp38 and JNK. Accordingly, the compounds described herein are also usefulin treatment of non-neoplastic diseases and/or inflammatory diseasesand/or autoimmune diseases.

DEFINITIONS

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contentclearly dictates otherwise. It should also be noted that the term “or”is generally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” or “nitrile” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radical,having from one to thirty carbon atoms, and which is attached to therest of the molecule by a single bond. Alkyls comprising any number ofcarbon atoms from 1 to 30 are included. An alkyl comprising up to 30carbon atoms is referred to as a C₁-C₃₀ alkyl, likewise, for example, analkyl comprising up to 12 carbon atoms is a C₁-C₁₂ alkyl. Alkyls (andother moieties defined herein) comprising other numbers of carbon atomsare represented similarily. Alkyl groups include, but are not limitedto, C₁-C₃₀ alkyl, C₁-C₂₀ alkyl, C₁-C₁₅ alkyl, C₁-C₁₀ alkyl, C₁-C₈ alkyl,C₁-C₆ alkyl, C₁-C₄ alkyl, C₁-C₃ alkyl, C₁-C₂ alkyl, C₂-C₈ alkyl, C₃-C₈alkyl and C₄-C₈ alkyl. Representative alkyl groups include, but are notlimited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwisespecifically in the specification, an alkyl group may be optionallysubstituted as described below. “Alkylene” or “alkylene chain” refers toa straight or branched divalent hydrocarbon chain linking the rest ofthe molecule to a radical group.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed below.

“Heteroalkylene” refers to an alkyl radical as described above where oneor more carbon atoms of the alkyl is replaced with a O, N or S atom.“Heteroalkylene” or “heteroalkylene chain” refers to a straight orbranched divalent heteroalkyl chain linking the rest of the molecule toa radical group. Unless stated otherwise specifically in thespecification, the heteroalkyl or heteroalkylene group may be optionallysubstituted as described below. Representative heteroalkyl groupsinclude, but are not limited to —OCH₂CH₂OMe, —OCH₂CH₂OCH₂CCH₂NH₂, or—OCH₂CH₂OCH₂CH₂OCH₂CH₂N(Me)₂. Representative heteroalkylene groupsinclude, but are not limited to —OCH₂CH₂O—, —OCH₂CH₂OCH₂CH₂O—, or—OCH₂CH₂OCH₂CH₂OCH₂CH₂CHO—.

“Alkylamino” refers to a radical of the formula —NHR_(a) or —NR_(a)R_(a)where each R_(a) is, independently, an alkyl radical as defined above.Unless stated otherwise specifically in the specification, an alkylaminogroup may be optionally substituted as described below.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl radicals include, but are not limited to, aryl radicalsderived from the hydrocarbon ring systems of aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals that are optionally substituted.

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

“Cycloalkyl” refers to a stable, non-aromatic, monocyclic or polycycliccarbocyclic ring, which may include fused or bridged ring systems, whichis saturated or unsaturated, and attached to the rest of the molecule bya single bond. Representative cycloalkyls include, but are not limitedto, cycloaklyls having from three to fifteen carbon atoms, from three toten carbon atoms, from three to eight carbon atoms, from three to sixcarbon atoms, from three to five carbon atoms, or three to four carbonatoms. Monocyclic cyclcoalkyl radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unlessotherwise stated specifically in the specification, a cycloalkyl groupmay be optionally substituted. Illustrative examples of cycloalkylgroups include, but are not limited to, the following moieties:

and the like.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure. When the fused ring is a heterocyclyl ringor a heteroaryl ring, any carbon atom on the existing ring structurewhich becomes part of the fused heterocyclyl ring or the fusedheteroaryl ring may be replaced with a nitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

“Perhalo” or “perfluoro” refers to a moiety in which each hydrogen atomhas been replaced by a halo atom or fluorine atom, respectively.

“Heterocyclyl” or “heterocyclic ring” or “hetercycloalkyl” refers to astable 3- to 24-membered non-aromatic ring radical comprising 2 to 23carbon atoms and from one to 8 heteroatoms selected from the groupconsisting of nitrogen, oxygen, phosphorous and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radicalmay be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which may include fused or bridged ring systems; and the nitrogen,carbon or sulfur atoms in the heterocyclyl radical may be optionallyoxidized; the nitrogen atom may be optionally quaternized; and theheterocyclyl radical may be partially or fully saturated. Examples ofsuch heterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, 12-crown-4,15-crown-5,18-crown-6,21-crown-7,aza-18-crown-6, diaza-18-crown-6, aza-21-crown-7, and diaza-21-crown-7.Unless stated otherwise specifically in the specification, aheterocyclyl group may be optionally substituted. Illustrative examplesof heterocycloalkyl groups, also referred to as non-aromaticheterocycles, include:

and the like. The term heterocycloalkyl also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, a heterocycloalkyl group may be optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. For purposes ofthis invention, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

All the above groups may be either substituted or unsubstituted. Theterm “substituted” as used herein means any of the above groups (i.e.,alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycarbonyl,alkylamino, amidyl, amidinylalkyl, amidinylalkylcarbonyl, aminoalkyl,aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl,aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl,cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkyloxycarbonyl,guanidinylalkyl, guanidinylalkylcarbonyl, haloalkyl, heterocyclyl and/orheteroaryl), may be further functionalized wherein at least one hydrogenatom is replaced by a bond to a non-hydrogen atom substituent. Unlessstated specifically in the specification, a substituted group mayinclude one or more substituents selected from: oxo, —CO₂H, nitrile,nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, alkoxyalkyl,alkylcarbonyl, alkyloxycarbonyl, aryl, aralkyl, arylcarbonyl,aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy,cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl,cycloalkylalkylcarbonyl, cycloalkyloxycarbonyl, heterocyclyl,heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines,trialkylammonium (—N⁺R₃), N-oxides, imides, and enamines; a silicon atomin groups such as trialkylsilyl groups, dialkylarylsilyl groups,alkyldiarylsilyl groups, triarylsilyl groups, perfluoroalkyl orperfluoroalkoxy, for example, trifluoromethyl or trifluoromethoxy.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. For example, “substituted” includes any of theabove groups in which one or more hydrogen atoms are replaced with—NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h),—OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g),—SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h). “Substituted” also meansany of the above groups in which one or more hydrogen atoms are replacedwith —C(═O)R_(g), —C(═O)OR_(g), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h), —SH,—SR_(g) or —SSR_(g). In the foregoing, R_(g) and R_(h) are the same ordifferent and independently hydrogen, alkyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl. In addition, each of the foregoingsubstituents may also be optionally substituted with one or more of theabove substituents. Furthermore, any of the above groups may besubstituted to include one or more internal oxygen or sulfur atoms. Forexample, an alkyl group may be substituted with one or more internaloxygen atoms to form an ether or polyether group. Similarily, an alkylgroup may be substituted with one or more internal sulfur atoms to forma thioether, disulfide, etc. Amidyl moieties may be substituted with upto 2 halo atoms, while other groups above may be substituted with one ormore halo atoms. With the exception of alkyl groups, all other groupsmay also be substituted with amino or monoalklyamino. With the exceptionof alkyl and alkylcarbonyl groups, all other groups may also besubstituted with guanidinyl or amidynyl. Optional substitutents for anyof the above groups also include arylphosphoryl, for example—R_(a)P(Ar)₃ wherein R_(a) is an alkylene and Ar is aryl moiety, forexample phenyl.

An “effective amount” or “therapeutically effective amount” refers to anamount of a compound administered to a subject (e.g. a mammal, such as ahuman), either as a single dose or as part of a series of doses, whichis effective to produce a desired therapeutic effect.

“Treatment” of a subject (e.g. a mammal, such as a human) includes anytype of intervention used in an attempt to alter the natural course ofthe subject. In some embodiments, treatment includes administration of apharmaceutical composition, subsequent to the initiation of a pathologicevent or contact with an etiologic agent and includes stabilization ofthe condition (e.g., condition does not worsen, e.g., cancer does notmetastasize and the like) or alleviation of the condition (e.g.,reduction in tumor size, remission of cancer, absence of symptoms ofautoimmune disease and the like). In other embodiments, treatment alsoincludes prophylactic treatment (e.g., administration of a compositiondescribed herein when an individual is suspected to be suffering from acondition described herein).

As used herein, “subject”, “individual” and “patient” are usedinterchangeably. None of the terms imply that a medical professional isrequired for the administration of the compounds disclosed herein.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

CompoundsFormula A—Six-Five Ring Systems

As used herein, Formula A includes compounds of Formula A-I, FormulaA-II, Formula A-III-1, Formula A-III-2, Formula A-III-3, Formula A-IV,Formula A-V-1, Formula A-V-2, Formula A-V-3, Formula A-VI-1, FormulaA-VI-2, Formula A-VI-3, Formula A-VII-1, Formula A-VII-2, FormulaA-VII-3, Formula A-VIII, Formula A-IX-1, Formula A-IX-2, Formula A-X,Formula A-XI, Formula A-XII, Formula A-XIII, Formula A-XIV, FormulaA-XV-1, Formula A-XV-2, Formula A-XV-3, Formula A-XV-4, Formula A-XVI-1,Formula A-XVI-2, Formula A-XVII, Formula A-XVIII, Formula A-XIX, FormulaA-XX, and Formula A-XXI.

In one aspect, described herein is a compound of Formula A-I, or apharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, as described in the summary of the invention.

In one aspect, provided herein are compounds having the structure ofFormula A-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8c))(R^(8d)); provided that W¹ and        W² are not both O, or both S;    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is O, N—R^(A), S, S(O), or S(O)₂, then X² is        C(R^(2a)R^(2b));    -   or:    -   X¹ is CR^(2c)R^(2d) and X² is CR^(2a)R^(2b), and R^(2c) and        R^(2a) together form a bond;    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring;    -   or:    -   X¹ is CH₂ and X² is C═O, C═C(R^(C))₂, or C═NR^(C); where each        R^(C) is independently selected from H, —CN, —OH, alkoxy,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d), are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) are independently selected        from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆ alkoxy,        C₁-C₆heteroalkyl, and substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:

R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d) togetherwith the atoms to which they are attached form a substituted orunsubstituted saturated, or partially saturated 3-7 membered spirocycleor heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;

-   -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl        or heteroaryl is substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, one group of compounds has the structure of Formula A-II:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, one group of compounds that has the structure of FormulaA-III-1, Formula A-III-2 or Formula A-III-3:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, one group of compounds that has the structure of FormulaA-III-1

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, one group of compounds has the structure of Formula A-IV:

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—.

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -U- is —NHC(═O)—, or —C(═O)NH—.

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   R³ is C₁-C₃alkyl.

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   -U- is —NHC(═O)—, or —C(═O)NH—;    -   R³ is C₁-C₃alkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ and R⁵ together with theatoms to which they are attached form a substituted or unsubstituted 5-7membered ring. Within this group of compounds are compounds wherein

is

and

-   q is 1, 2 or 3.

Among the compounds of Formula A described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ is bonded to a nitrogenatom of U to form a substituted or unsubstituted 5-7 membered ring.Within this group of compounds are compounds wherein

is

and

-   q is 1, 2 or 3.

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-V-1, Formula A-V-2, or Formula A-V-3:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-V-2:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-VI-1, Formula A-VI-2, or Formula A-VI-3:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-VII-1, Formula A-VII-2, or Formula A-VII-3:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein X¹ is N—R^(A).

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-VIII:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-IX-1 or Formula A-IX-2:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula A-X:

-   -   wherein,        -   ring A is a fused substituted or unsubstituted saturated or            partially saturated 3-10 membered cycloalkyl ring,            substituted or unsubstituted saturated or partially            saturated 3-10 membered heterocycloalkyl ring, substituted            or unsubstituted 5-10 membered aryl ring, or substituted or            unsubstituted 5-10 membered heteroaryl ring.

In some embodiments of Formula A-X, ring A is selected from indolyl, andphenyl.

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula A-XI:

In some embodiments of Formula A-XI, R^(8a) and R^(8b) are independentlyselected from H and C₁-C₃alkyl.

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-XII:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-XIII:

Within the group of compounds of Formula A are compounds wherein X¹ isO, S or S(O)₂, and X² is CH₂.

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherwith the atoms to which they are attached form a substituted orunsubstituted fused 5-7 membered saturated, or partially saturatedcarbocyclic ring or heterocyclic ring comprising 1-3 heteroatomsselected from S, O and N, a substituted or unsubstituted fused 5-10membered aryl ring, or a substituted or unsubstituted fused 5-10membered heteroaryl ring comprising 1-3 heteroatoms selected from S, Oand N.

Within such a group of compounds are compounds of Formula A-I, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, having the structure of Formula A-XIV:

-   -   wherein ring B is an aryl or heteroaryl ring.

In some embodiments, ring B is an aryl. In some embodiments, ring B isphenyl. In some embodiments, ring B is a heteroaryl ring. In someembodiments, ring B is a monocyclic heteroaryl ring or a bicyclicheteroaryl ring. In some embodiments, ring B is a monocyclic heteroarylring. In some embodiments, ring B is a bicyclic heteroaryl ring. In someembodiments, ring B is selected from phenyl, pyridinyl and thiophenyl.In some embodiments, ring B is selected from pyridinyl and thiophenyl.

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8a) and R^(8b) togetherwith the atoms to which they are attached form a substituted orunsubstituted saturated or partially saturated 3-7 membered spirocycleor heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;or R^(8c) and R^(8d) together with the atoms to which they are attachedform a substituted or unsubstituted saturated, or partially saturated3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatomsselected from S, O and N. Within such a group of compounds are compoundshaving the structure of Formula A-XV-1, Formula A-XV-2, Formula A-XV-3or Formula A-XV-4:

-   -   wherein R^(A) is H, C₁-C₃alkyl or —C(═O)C₁-C₃alkyl.

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherform a bond. Within such a group of compounds are compounds having thestructure of Formula A-XVII:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-XVIII:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaA-XIX:

Among the compounds of Formula A-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula A-XX:

Among the compounds of Formula A are compounds having the structure ofFormula A-XXI, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W² is O, S, or C(R^(8c))(R^(8d));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a), and R^(2b) are independently selected from H,        substituted or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   R^(8c) and R^(8d) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹;        and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   R^(2a), R^(2b), R^(2c), R^(2d) are independently selected from        H, C₁-C₃alkyl or —C(═O)R^(B); and    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl).

Among any of the compounds of Formula A described above and below, arecompounds wherein, R^(2a), R^(2b), R^(2c), R^(2d) are independentlyselected from H, and C₁-C₃alkyl.

Among any of the compounds of Formula A described above and below, arecompounds wherein R¹ is H or methyl.

Among any of the compounds of Formula A described above and below, arecompounds wherein R¹ is H.

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷, or        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷.

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   R⁶ is substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl.

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   R⁶ is a substituted or unsubstituted C₂-C₁₀heterocycloalkyl.

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   R⁶ is a substituted or unsubstituted heteroaryl.

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, —S(═O)₂NHR⁷, —(C₁-C₃alkyl)-C(═O)NHR⁵, or        —(C₁-C₃alkyl)-S(═O)₂NHR⁷.

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, or —S(═O)₂NHR⁷.

Among any of the compounds of Formula A described above and below, arecompounds wherein R⁶ is —C(═O)NHR⁷.

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   each R⁷ is independently selected from a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl),-(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl).

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   R⁷ is independently selected from a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, and        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂.

Among any of the compounds of Formula A described above and below, arecompounds wherein, R⁷ is selected from

Among any of the compounds of Formula A described above and below, arecompounds wherein,

-   -   W² is C(R^(8c))(R^(8d));    -   R¹ is H;    -   X¹ is O;    -   R^(2a), R^(2b) are independently selected from H, and        C₁-C₃alkyl;

-   -    is

-   -   R^(8a), R^(8b), R^(8c), R^(8d) are independently selected from H        and C₁-C₃alkyl.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

Among any of the compounds of Formula A described above and below, arecompounds or pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof, selected from:

A pharmaceutical composition comprising a compound of Formula Adescribed above or below, or pharmaceutically acceptable salt, N-oxide,racemate or stereoisomer thereof, and a pharmaceutically acceptablecarrier.

Formula B—Seven-Five Ring Systems

As used herein, Formula B includes compounds of Formula B-I, FormulaB-II, Formula B-III-1, Formula B-III-2, Formula B-III-3, Formula B-IV,Formula B-V-1, Formula B-V-2, Formula B-V-3, Formula B-VI-1, FormulaB-VI-2, Formula B-VI-3, Formula B-VII-1, Formula B-VII-2, FormulaB-VII-3, Formula B-VIII-1, Formula B-VIII-2, Formula B-VIII-3, FormulaB-IX-1, Formula B-IX-2, Formula B-X, Formula B-XI-1, Formula B-XI-2,Formula B-XII, Formula B-XIII, Formula B-XIV, Formula B-XV, FormulaB-XVI-1, Formula B-XVI-2, Formula B-XVI-3, Formula B-XVI-4, FormulaB-XVII-1, Formula B-XVII-2, Formula B-XVIII, Formula B-XIX, FormulaB-XX, Formula B-XXI, and Formula B-XXII.

In one aspect, described herein is a compound of Formula B-I, or apharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, as described in the summary of the invention.

In another aspect, provided herein are compounds having the structure ofFormula B-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is selected from N—R^(A), S, S(O) and S(O)₂, then X² is        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is O, then X² is selected from CR^(2c)R^(2d) and        N—R^(A), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ is CH₂, then X² is selected from O, N—R^(A), S, S(O),        and S(O)₂, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ is CR^(2e)R^(2f) and X² is CR^(2c)R^(2d), and R^(2e) and        R^(2c) together form a bond, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ and X³ are both CH₂ and X² is C═O, C═C(R^(C))₂, or C═NR^(C);        where each R^(C) is independently selected from H, —CN, —OH,        alkoxy, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X³ is        CR^(2a)R^(2b);    -   or:    -   X² and X³ are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X¹ is        CR^(2e)R^(2f);    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8c))(R^(8d)); provided that W¹ and        W² are not both O, or both S;    -   R^(2a), R^(2b), R^(2c), R^(2d) R^(2e), and R^(2f) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) are independently selected        from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆ alkoxy,        C₁-C₆heteroalkyl, and substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula B-II:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-III-1, Formula B-III-2 or Formula B-III-3:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-III-1:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula B-IV:

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -U- is —NHC(═O)—, or —C(═O)NH—.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   R³ is C₁-C₃alkyl.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   -U- is —NHC(═O)—, or —C(═O)NH—;    -   R³ is C₁-C₃alkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ and R⁵ together with theatoms to which they are attached form a substituted or unsubstituted 5-7membered ring.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

and

-   q is 1, 2 or 3.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ is bonded to a nitrogenatom of U to form a substituted or unsubstituted 5-7 membered ring.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

and

-   q is 1, 2 or 3.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   X¹ is selected from N—R^(A), S, S(O) and S(O)₂; and    -   X² is CH₂.

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-V-1, Formula B-V-2, or Formula B-V-3:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-VI-1, Formula B-VI-2, Formula B-VI-3:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-VII-1, Formula B-VII-2 or Formula B-VII-3

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-V-2, Formula B-VI-2, or Formula B-VII-2:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-VIII-1, Formula B-VIII-2, or Formula B-VIII-3:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein

-   -   X¹ is CH₂; and    -   X² is selected from O, N—R^(A), S, S(O), and S(O)₂.

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-IX-1 or Formula B-IX-2:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula B-X:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-XI-1 or Formula B-XI-2:

-   -   wherein,    -   ring A is a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, substituted        or unsubstituted saturated or partially saturated 3-10 membered        heterocycloalkyl ring, substituted or unsubstituted 5-10        membered aryl ring, or substituted or unsubstituted 5-10        membered heteroaryl ring.

Within such a group of compounds are compounds wherein ring A isselected from indolyl and phenyl.

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-XI-1:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-XII:

Within such a group of compounds are compounds wherein R^(8a) and R^(8b)are independently selected from H and C₁-C₃alkyl.

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-XIII:

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-XIV:

Within the group of compounds of Formula B-XII, B-XIII and B-XIV arecompounds wherein X¹ is O, S or S(O)₂, and X² is CH₂.

Within the group of compounds of Formula B-XII, B-XIII and B-XIV arecompounds wherein X¹ is O, and X² is N—R^(A).

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein

-   -   X¹ is O, S or S(O)₂, and X² is CH₂;    -   or X¹ is N—R^(A) and X² is C═O or CH₂;    -   or X¹ and X² are C and are members of a fused substituted or        unsubstituted a fused substituted or unsubstituted 5-10 membered        aryl ring, or a fused substituted or unsubstituted 5-10 membered        heteroaryl ring;    -   R^(A) is H, C₁-C₆alkyl, or —C(═O)C₁-C₆alkyl.

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherwith the atoms to which they are attached form a substituted orunsubstituted fused 5-7 membered saturated, or partially saturatedcarbocyclic ring or heterocyclic ring comprising 1-3 heteroatomsselected from S, O and N, a substituted or unsubstituted fused 5-10membered aryl ring, or a substituted or unsubstituted fused 5-10membered heteroaryl ring comprising 1-3 heteroatoms selected from S, Oand N.

Within such a group of compounds are compounds having the structure ofFormula B-XV:

-   -   wherein ring B is an aryl or heteroaryl ring.

In some embodiments, ring B is an aryl. In some embodiments, ring B isphenyl. In some embodiments, ring B is a heteroaryl ring. In someembodiments, ring B is a monocyclic heteroaryl ring or a bicyclicheteroaryl ring. In some embodiments, ring B is a monocyclic heteroarylring. In some embodiments, ring B is a bicyclic heteroaryl ring. In someembodiments, ring B is selected from phenyl, pyridinyl and thiophenyl.In some embodiments, ring B is selected from pyridinyl and thiophenyl.

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8a) and R^(8b) togetherwith the atoms to which they are attached form a substituted orunsubstituted saturated, or partially saturated 3-7 membered spirocycleor heterospirocycle comprising 1-3 heteroatoms selected from S, O and Nor R^(8c) and R^(8d) together with the atoms to which they are attachedform a substituted or unsubstituted saturated, or partially saturated3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatomsselected from S, O and N.

Within such a group are compounds having the structure of FormulaB-XVI-1, Formula B-XVI-2, Formula B-XVI-3, or Formula B-XVI-4:

-   -   or having the structure of Formula B-XVII-1 or Formula B-XVII-2:

-   -   wherein R^(A) is H, C₁-C₃alkyl or —C(═O)C₁-C₃alkyl.

Among the compounds of Formula B-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherform a bond.

Within such a group are compounds having the structure of FormulaB-XVIII:

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-XIX:

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula B-XX:

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaB-XXI:

In another aspect, provided herein are compounds having the structure ofFormula B-XXII, or pharmaceutically acceptable salt, N-oxide, racemateor stereoisomer thereof:

-   -   wherein,    -   W² is O, S, or C(R^(8c))(R^(8d));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a) and R^(2b) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   R^(8c) and R^(8d) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl; where each substituted alkyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted        with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R^(2a), R^(2b) R^(2c), R^(2d), R^(2e), and R^(2f) are        independently selected from H, C₁-C₃alkyl and —C(═O)R^(B); and        R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl).

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(2a), R^(2b) R^(2c),R^(2d), R^(2e) and R^(2f) are independently H or C₁-C₃ alkyl.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R¹ is H or methyl.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R¹ is H.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷, or        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is a substituted or unsubstituted C₂-C₁₀heterocycloalkyl.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is a substituted or unsubstituted heteroaryl.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, —S(═O)₂NHR⁷, —(C₁-C₃alkyl)-C(═O)NHR⁵, or        —(C₁-C₃alkyl)-S(═O)₂NHR⁷.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, or —S(═O)₂NHR⁷.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R⁶ is —C(═O)NHR⁷.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   each R⁷ is independently selected from a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted        aryl)₂-(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl).

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁷ is independently selected from a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, and        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁷ is selected from

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   W² is C(R^(8c))(R^(8d));    -   R¹ is H;    -   R^(2a), R^(2b) are independently selected from H, and        C₁-C₃alkyl;

-   -    is

-   -   R^(8a), R^(8b), R^(8c), R^(8d) are independently selected from H        and C₁-C₃alkyl.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

Among the compounds of Formula B described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, are compounds selected from:

In some embodiments, a compound of Formula B described above or below,or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is

Also provided herein are pharmaceutical compositions comprising acompound of Formula B described above, or pharmaceutically acceptablesalt, N-oxide, racemate or stereoisomer thereof, and a pharmaceuticallyacceptable carrier.

Formula C—Eight-Five Ring Systems

As used herein, Formula C includes compounds of Formula C-I, FormulaC-II, Formula C-III-1, Formula C-III-2, Formula C-III-3, Formula C-IV,Formula C-V-1, Formula C-V-2, Formula C-V-3, Formula C-VI-I, FormulaC-VI-2, Formula C-VI-3, Formula C-VII-I, Formula C-VII-2, FormulaC-VII-3, Formula C-VIII-I, Formula C-VIII-2, Formula C-VIII-3, FormulaC-IX-1, Formula C-IX-2, Formula C-X-1, Formula C-X-2, Formula C-XI,Formula C-XII, Formula C-XIII, Formula C-XIV, Formula C-XV-1, FormulaC-XV-2, Formula C-XV-3, Formula C-XV-4, Formula C-XVI-1, FormulaC-XVI-2, Formula C-XVII, Formula C-XVIII, Formula C-XIX, Formula C-XX,and Formula C-XXI.

In one aspect, described herein is a compound of Formula C-I, or apharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, as described in the summary of the invention.

In another aspect, provided herein are compounds having the structure ofFormula C-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is selected from N—R^(A), S, S(O) and S(O)₂, then X² is        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is O, then X² is selected from CR^(2c)R^(2d) and        N—R^(A), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ is CH₂, then X² is selected from O, N—R^(A), S, S(O),        and S(O)₂, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ is CR^(2e)R^(2f) and X² is CR^(2c)R^(2d), and R^(2e) and        R^(2c) together form a bond, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring; and X³ is        CR^(2a)R^(2b);    -   or:    -   X² and X³ are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X¹ is        CR^(2e)R^(2f);    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8a))(R^(8d)); provided that W¹ and        W² are not both O, or both S;    -   R^(2a), R^(2b), R^(2c), R^(2d) R^(2e), and R^(2f) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) are independently selected        from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆ alkoxy,        C₁-C₆heteroalkyl, and substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula C-II:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-III-1, Formula C-III-2 or Formula C-III-3:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-III-1:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula C-IV:

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -U- is —NHC(═O)—, or —C(═O)NH—.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   R³ is C₁-C₃alkyl.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   -U- is —NHC(═O)—, or —C(═O)NH—;    -   R³ is C₁-C₃alkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ and R⁵ together with theatoms to which they are attached form a substituted or unsubstituted 5-7membered ring.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, recemate or stereoisomerthereof, is one group of compounds wherein,

is

and

-   q is 1, 2 or 3.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ is bonded to a nitrogenatom of U to form a substituted or unsubstituted 5-7 membered ring.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

and

-   q is 1, 2 or 3.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   X¹ is selected from N—R^(A), S, S(O) and S(O)₂; and    -   X² is CH₂.

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula C-V-1or Formula C-V-2 or Formula C-V-3:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-VI-1 or Formula C-VI-2 or Formula C-VI-3:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-VII-1 or Formula C-VII-2 or Formula C-VII-3:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-VIII-1 or Formula C-VIII-2 or Formula C-VIII-3:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula C-V-2or Formula C-VI-2 or Formula C-VII-2 or Formula C-VIII-2:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein

-   -   X¹ is CH₂; and    -   X² is selected from O, N—R^(A), S, S(O), and S(O)₂.

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-IX-1 or Formula C-IX-2:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula C-X-1or Formula C-X-2:

-   -   wherein ring A is a fused substituted or unsubstituted saturated        or partially saturated 3-10 membered cycloalkyl ring,        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, substituted or        unsubstituted 5-10 membered aryl ring, or substituted or        unsubstituted 5-10 membered heteroaryl ring.

Within such a group of compounds are compounds wherein ring A isselected from indolyl and phenyl.

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula C-XI:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-XII:

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-XIII:

Among the compounds of Formula C-XI, Formula C-XII and Formula C-XIII,is one group of compounds wherein X¹ is O, S or S(O)₂, and X² is CH₂.

Among the compounds of Formula C-XI, Formula C-XII and Formula C-XIII,is one group of compounds wherein X¹ is N—R^(A), and X²CH₂.

Among the compounds is one group of compounds wherein R^(2a), R^(2b)R^(2c), R^(2d), R^(2e), and R^(2f) are independently H or C₁-C₃ alkyl;and R¹ is H or methyl. Among the compounds is one group of compoundswherein R¹ is H.

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherwith the atoms to which they are attached form a substituted orunsubstituted fused 5-7 membered saturated, or partially saturatedcarbocyclic ring or heterocyclic ring comprising 1-3 heteroatomsselected from S, O and N, a substituted or unsubstituted fused 5-10membered aryl ring, or a substituted or unsubstituted fused 5-10membered heteroaryl ring comprising 1-3 heteroatoms selected from S, Oand N.

Within such a group of compounds are compounds having the structure ofFormula C-XIV:

where ring B is an aryl or heteroaryl ring.

In some embodiments, ring B is an aryl. In some embodiments, ring B isphenyl. In some embodiments, ring B is a heteroaryl ring. In someembodiments, ring B is a monocyclic heteroaryl ring or a bicyclicheteroaryl ring. In some embodiments, ring B is a monocyclic heteroarylring. In some embodiments, ring B is a bicyclic heteroaryl ring. In someembodiments, ring B is selected from phenyl, pyridinyl and thiophenyl.In some embodiments, ring B is selected from pyridinyl and thiophenyl.

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8a) and R^(8b) togetherwith the atoms to which they are attached form a substituted orunsubstituted saturated, or partially saturated 3-7 membered spirocycleor heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;or R^(8c) and R^(8d) together with the atoms to which they are attachedform a substituted or unsubstituted saturated, or partially saturated3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatomsselected from S, O and N.

Within such a group of compounds are compounds having the structure ofFormula C-XV-1, Formula C-XV-2, Formula C-XV-3, or Formula C-XV-4:

-   -   or having the structure of Formula C-XVI-1 or Formula C-XVI-2:

-   -   wherein R^(A) is H, C₁-C₃alkyl or —C(═O)C₁-C₃alkyl.

Among the compounds of Formula C-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherform a bond.

Within such a group of compounds are compounds having the structure ofFormula C-XVII:

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-XVIII:

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-XIX:

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula C-XX:

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaC-XXI, or pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W² is O, S, or C(R^(8c))(R^(8d));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a) and R^(2b) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   R^(8c) and R^(8d) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹;        and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R^(2a), R^(2b) R^(2c), R^(2d), R^(2e), and R^(2f) are        independently selected from H, C₁-C₃alkyl and —C(═O)R^(B); and    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl).

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(2a), R^(2b) R^(2c),R^(2d), R^(2e) and R^(2f) are independently H or C₁-C₃ alkyl.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R¹ is H or methyl.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R¹ is H.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷, or        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is a substituted or unsubstituted C₂-C₁₀heterocycloalkyl.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is a substituted or unsubstituted heteroaryl.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, —S(═O)₂NHR⁷, —(C₁-C₃alkyl)-C(═O)NHR⁵, or        —(C₁-C₃alkyl)-S(═O)₂NHR⁷.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, or —S(═O)₂NHR⁷.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R⁶ is —C(═O)NHR⁷.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   each R⁷ is independently selected from a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted        aryl)₂-(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl).

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁷ is independently selected from a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, and        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   R⁷ is selected from

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   W² is C(R^(8c))(R^(8d));    -   R¹ is H;    -   R^(2a), R^(2b) are independently selected from H, and        C₁-C₃alkyl;

-   -    is

-   -   R^(8a), R^(8b), R^(8c), R^(8d) are independently selected from H        and C₁-C₃alkyl.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

Among the compounds of Formula C described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, are compounds selected from:

Also provided herein are pharmaceutical composition comprising acompound of Formula C, or pharmaceutically acceptable salt, N-oxide,racemate or stereoisomer thereof, and a pharmaceutically acceptablecarrier.

Formula D—Seven-Six Ring Systems

As used herein, Formula D includes compounds of Formula D-I, FormulaD-II, Formula D-II-1, Formula D-II-2, Formula D-II-3, Formula D-III,Formula D-IV, Formula D-V-1, Formula D-V-2, Formula D-V-3, FormulaD-VI-1, Formula D-VI-2, Formula D-VI-3, Formula D-VII-1, FormulaD-VII-2, Formula D-VII-3, Formula D-VIII-1, Formula D-VIII-2, FormulaD-VIII-3, Formula D-IX-1, Formula D-IX-2, Formula D-X, Formula D-XI-1,Formula D-XI-2, Formula D-XII-1, Formula D-XII-2, Formula D-XIII,Formula D-XIV, Formula D-XV, Formula D-XVI-1, Formula D-XVI-2, FormulaD-XVI-3, Formula D-XVI-4, Formula D-XVII-1, Formula D-XVII-2, FormulaD-XVIII-1, Formula D-XVIII-2, Formula D-XIX, Formula D-XX, Formula D-XXIand Formula D-XXII.

In one aspect, described herein is a compound of Formula D-I, or apharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, as described in the summary of the invention.

A compound having the structure of Formula D-I, pharmaceuticallyacceptable salt, N-oxide, racemate or stereoisomer thereof:

-   -   wherein,    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is selected from N—R^(A), S, S(O) and S(O)₂, then X² is        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is O, then X² is selected from CR^(2c)R^(2d) and        N—R^(A), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ is CH₂, then X² is selected from O, N—R^(A), S, S(O),        and S(O)₂, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ is CR^(2e)R^(2f) and X² is CR^(2c)R^(2d), and R^(2e) and        R^(2c) together form a bond, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ and X³ are both CH₂ and X² is C═O, C═C(R^(C))₂, or C═NR^(C);        where each R^(C) is independently selected from H, —CN, —OH,        alkoxy, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X³ is        CR^(2a)R^(2b);    -   or:    -   X² and X³ are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X¹ is        CR^(2e)R^(2f);    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8c))(R^(8d));    -   W³ is O, S, N—R^(A), or C(R^(8e))(R^(8f)); provided that the        ring comprising W¹, W² and W³ does not comprise two adjacent        oxygen atoms or sulfur atoms;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d) R^(2e), and R^(2f) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are        independently selected from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and substituted or unsubstituted        aryl;    -   or:    -   R^(8a), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8b) and R^(8c) together form a bond;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) are as defined above, and        R^(8c) and R^(8e) together form a bond;    -   or:    -   R^(8a), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8b) and R^(8c) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) are as defined above, and        R^(8c) and R^(8e) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8c), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8a) and R^(8b) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8e) and R^(8f) are as defined above, and        R^(8c) and R^(8d) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8c), and R^(8d) are as defined above, and        R^(8e) and R^(8f) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula D-II:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-II-1, Formula D-II-2, or Formula D-II-3:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-III:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula D-IV:

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -U- is —NHC(═O)—, or —C(═O)NH—.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   R³ is C₁-C₃alkyl.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   -U- is —NHC(═O)—, or —C(═O)NH—;    -   R³ is C₁-C₃alkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ and R⁵ together with theatoms to which they are attached form a substituted or unsubstituted 5-7membered ring.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

and

-   q is 1, 2 or 3.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ is bonded to a nitrogenatom of U to form a substituted or unsubstituted 5-7 membered ring.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

and

-   q is 1, 2 or 3.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   X¹ is selected from N—R^(A), S, S(O) and S(O)₂; and    -   X² is CH₂.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-V-1, Formula D-V-2, or Formula D-V-3:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-VI-1, Formula D-VI-2, Formula D-VI-3:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-VII-1, Formula D-VII-2 or Formula D-VII-3

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-V-2, Formula D-VI-2, or Formula D-VII-2:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group wherein R¹ is H or methyl; R^(2a), R^(2b) R^(2c),R^(2d) R^(2e), and R^(2f) are independently H or C₁-C₃ alkyl; R^(8a),R^(8b) R^(8c), R^(8d), R^(8e), and R^(8f) are independently H or C₁-C₃alkyl.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group wherein R¹ is H.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-VIII-1, Formula D-VIII-2, or Formula D-VIII-3:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein

-   -   X¹ is CH₂; and    -   X² is selected from O, N—R^(A), S, S(O), and S(O)₂.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-IX-1 or Formula D-IX-2:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula D-X:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-XI-1 or Formula D-XI-2:

-   -   wherein,    -   ring A is a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, substituted        or unsubstituted saturated or partially saturated 3-10 membered        heterocycloalkyl ring, substituted or unsubstituted 5-10        membered aryl ring, or substituted or unsubstituted 5-10        membered heteroaryl ring.

Within this group of compounds are compounds wherein ring A is selectedfrom indolyl and phenyl.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-XII-1 or Formula D-XII-2:

Within such a group of compounds wherein R^(8a) and R^(8b) areindependently selected from H and C₁-C₃alkyl.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-XIII:

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-XIV:

Among the compounds of Formula D-XII, Formula D-XIII and Formula D-XIVare compounds wherein X¹ is O, S or S(O)₂, and X² is CH₂.

Among the compounds of Formula D-XII, Formula D-XIII and Formula D-XIVare compounds wherein X¹ is O, and X² is N—R^(A).

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherwith the atoms to which they are attached form a substituted orunsubstituted fused 5-7 membered saturated, or partially saturatedcarbocyclic ring or heterocyclic ring comprising 1-3 heteroatomsselected from S, O and N, a substituted or unsubstituted fused 5-10membered aryl ring, or a substituted or unsubstituted fused 5-10membered heteroaryl ring comprising 1-3 heteroatoms selected from S, Oand N.

Within such a group of compounds are compounds having the structure ofFormula D-XV:

wherein ring B is an aryl or heteroaryl ring.

In some embodiments, ring B is an aryl. In some embodiments, ring B isphenyl. In some embodiments, ring B is a heteroaryl ring. In someembodiments, ring B is a monocyclic heteroaryl ring or a bicyclicheteroaryl ring. In some embodiments, ring B is a monocyclic heteroarylring. In some embodiments, ring B is a bicyclic heteroaryl ring. In someembodiments, ring B is selected from phenyl, pyridinyl and thiophenyl.In some embodiments, ring B is selected from pyridinyl and thiophenyl.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8a) and R^(8b) togetherwith the atoms to which they are attached form a substituted orunsubstituted saturated, or partially saturated 3-7 membered spirocycleor heterospirocycle comprising 1-3 heteroatoms selected from S, O and Nor R^(8c) and R^(8d) together with the atoms to which they are attachedform a substituted or unsubstituted saturated, or partially saturated3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatomsselected from S, O and N.

Within such a group of compounds are compounds having the structure ofFormula D-XVI-1, Formula D-XVI-2, Formula D-XVI-3, or Formula D-XVI-4:

-   -   or compounds having the structure of Formula D-XVII-1 or Formula        D-XVII-2:

-   -   wherein R^(A) is H, C₁-C₃alkyl or —C(═O)C₁-C₃alkyl.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherform a bond.

Among the compounds of Formula D-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8c) and R^(8e) togetherform a bond.

Within such a group of compounds are compounds having the structure ofFormula D-XVIII-1 or Formula D-XVIII-2:

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-XIX:

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula D-XX:

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-XXI:

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaD-XXII, or pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   W³ is O, S, or C(R^(8e))(R^(8f));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a) and R^(2b) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl        and C₁-C₆fluoroalkyl;    -   R^(8e) and R^(8f) are independently selected from H, C₁-C₆alkyl        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹;        and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R^(2a), R^(2b) R^(2c), R^(2d), R^(2e), and R^(2f) are        independently selected from H, C₁-C₃alkyl and —C(═O)R^(B); and    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl).

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(2a), R^(2b) R^(2c),R^(2d), R^(2e) and R^(2f) are independently H or C₁-C₃ alkyl.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R^(8a), R^(8b) R^(8c), R^(8d), R^(8e), and R^(8f) are        independently selected from H, C₁-C₃alkyl and —C(═O)R^(B); and    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl).

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8a), R^(8b) R^(8c),R^(8d), R^(8e), and R^(8f) are independently H or C₁-C₃ alkyl.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R¹ is H or methyl.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R¹ is H.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷, or        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is a substituted or unsubstituted C₂-C₁₀heterocycloalkyl.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is a substituted or unsubstituted heteroaryl.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, —S(═O)₂NHR⁷, —(C₁-C₃alkyl)-C(═O)NHR⁵, or        —(C₁-C₃alkyl)-S(═O)₂NHR⁷.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, or —S(═O)₂NHR⁷.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R⁶ is —C(═O)NHR⁷.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   each R⁷ is independently selected from a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted        aryl)₂-(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl).

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁷ is independently selected from a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, and        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

R⁷ is selected from

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   W³ is C(R^(8e))(R^(8f));    -   R¹ is H;    -   R^(2a), R^(2b) are independently selected from H, and        C₁-C₃alkyl;

is

-   -   R^(8a), R^(8b), R^(8e), R^(8f) are independently selected from H        and C₁-C₃alkyl.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

Among the compounds of Formula D described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is a compound of structure:

Also provided herein are pharmaceutical composition comprising acompound of Formula D or pharmaceutically acceptable salt, N-oxide,racemate or stereoisomer thereof, and a pharmaceutically acceptablecarrier.

Formula E—Eight-Six Ring Systems

As used herein, Formula E includes compounds of Formula E-I, FormulaE-II, Formula E-II-1, Formula E-II-2, Formula E-II-3, Formula E-III,Formula E-IV, Formula E-V-1, Formula E-V-2, Formula E-V-3, FormulaE-VI-1, Formula E-VI-2, Formula E-VI-3, Formula E-VII-1, FormulaE-VII-2, Formula E-VII-3, Formula E-VIII-1, Formula E-VIII-2, FormulaE-VIII-3, Formula E-IX-1, Formula E-IX-2, Formula E-X-1, Formula E-X-2,Formula E-XI-1, Formula E-XI-2, Formula E-XII, Formula E-XIII, FormulaE-XIV, Formula E-XV-1, Formula E-XV-2, Formula E-XV-3, Formula E-XV-4,Formula E-XVI-1, Formula E-XVI-2, Formula E-XVII-1, Formula E-XVII-2,Formula E-XVIII, Formula E-XIX, Formula E-XX, and Formula E-XXI.

In one aspect, described herein is a compound of Formula E-I, or apharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, as described in the summary of the invention.

In another aspect, provided herein are compounds having the structure ofFormula E-I, pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof:

-   -   wherein,    -   R¹ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted C₃-C₆cycloalkyl), substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted aryl),        —C₁-C₆alkyl-(substituted or unsubstituted heteroaryl);    -   when X¹ is selected from N—R^(A), S, S(O) and S(O)₂, then X² is        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or    -   when X¹ is O, then X² is selected from CR^(2c)R^(2d) and        N—R^(A), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ is CH₂, then X² is selected from O, N—R^(A), S, S(O),        and S(O)₂, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ is CR^(2e)R^(2f) and X² is CR^(2c)R^(2d), and R^(2e) and        R^(2c) together form a bond, and X³ is CR^(2a)R^(2b);    -   or:    -   X¹ and X² are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X³ is        CR^(2a)R^(2b);    -   or:    -   X² and X³ are independently selected from C and N, and are        members of a fused substituted or unsubstituted saturated or        partially saturated 3-10 membered cycloalkyl ring, a fused        substituted or unsubstituted saturated or partially saturated        3-10 membered heterocycloalkyl ring, a fused substituted or        unsubstituted 5-10 membered aryl ring, or a fused substituted or        unsubstituted 5-10 membered heteroaryl ring, and X¹ is        CR^(2e)R^(2f);    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   W¹ is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² is O, S, N—R^(A), or C(R^(8c))(R^(8d));    -   W³ is O, S, N—R^(A), or C(R^(8e))(R^(8f)); provided that the        ring comprising W¹, W² and W³ does not comprise two adjacent        oxygen atoms or sulfur atoms;    -   R^(2a), R^(2b), R^(2c), R^(2d) R^(2e), and R^(2f) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1 or 2;    -   -U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,        —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—;    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ together with the atoms to which they are attached        form a substituted or unsubstituted 5-7 membered ring;    -   or:    -   R³ is bonded to a nitrogen atom of U to form a substituted or        unsubstituted 5-7 membered ring;    -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, or substituted or unsubstituted        heteroaryl;    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are        independently selected from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and substituted or unsubstituted        aryl;    -   or:    -   R^(8a), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8b) and R^(8c) together form a bond;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) are as defined above, and        R^(8c) and R^(8e) together form a bond;    -   or:    -   R^(8a), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8b) and R^(8c) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) are as defined above, and        R^(8c) and R^(8e) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8c), R^(8d), R^(8e) and R^(8f) are as defined above, and        R^(8a) and R^(8b) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8e) and R^(8f) are as defined above, and        R^(8c) and R^(8d) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8c), and R^(8d) are as defined above, and        R^(8e) and R^(8f) together with the atoms to which they are        attached form a substituted or unsubstituted saturated, or        partially saturated 3-7 membered spirocycle or heterospirocycle        comprising 1-3 heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is        substituted with 1-3 R⁹; and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula E-II:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-II-1, Formula E-II-2, or Formula E-II-3:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-III:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula E-IV:

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-U- is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-U- is —NHC(═O)—, or —C(═O)NH—.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

R³ is C₁-C₃alkyl.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁴ is —NHR⁵, —N(R⁵)₂, or —N⁺(R⁵)₃; and    -   each R⁵ is independently selected from H, C₁-C₃alkyl, and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl).

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ and R⁵ together with theatoms to which they are attached form a substituted or unsubstituted 5-7membered ring.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

andq is 1, 2 or 3.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R³ is bonded to a nitrogenatom of U to form a substituted or unsubstituted 5-7 membered ring.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

is

andq is 1, 2 or 3.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   X¹ is selected from N—R^(A), S, S(O) and S(O)₂; and    -   X² is CH₂.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula E-V-1or Formula E-V-2 or Formula E-V-3:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-VI-1 or Formula E-VI-2 or Formula E-VI-3:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-VII-1 or Formula E-VII-2 or Formula E-VII-3:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-VIII-1 or Formula E-VIII-2 or Formula E-VIII-3:

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein

-   -   X¹ is CH₂; and    -   X² is selected from O, N—R^(A), S, S(O), and S(O)₂.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-IX-1 or Formula E-IX-2:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula E-X-1or Formula E-X-2:

wherein ring A is a fused substituted or unsubstituted saturated orpartially saturated 3-10 membered cycloalkyl ring, substituted orunsubstituted saturated or partially saturated 3-10 memberedheterocycloalkyl ring, substituted or unsubstituted 5-10 membered arylring, or substituted or unsubstituted 5-10 membered heteroaryl ring.

Within such a group of compounds are compounds wherein ring A isselected from indolyl and phenyl.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula E-XIor Formula E-XI-2:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-XII:

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-XIII:

Within the group of compounds of Formula E-XI, Formula E-XII and FormulaE-XIII are compounds wherein X¹ is O, S or S(O)₂, and X² is CH₂.

Within the group of compounds of Formula E-XI, Formula E-XII and FormulaE-XIII are compounds wherein X¹ is N—R^(A), and X²CH₂.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherwith the atoms to which they are attached form a substituted orunsubstituted fused 5-7 membered saturated, or partially saturatedcarbocyclic ring or heterocyclic ring comprising 1-3 heteroatomsselected from S, O and N, a substituted or unsubstituted fused 5-10membered aryl ring, or a substituted or unsubstituted fused 5-10membered heteroaryl ring comprising 1-3 heteroatoms selected from S, Oand N.

Within such a group of compounds are compounds having the structure ofFormula E-XIV:

where ring B is an aryl or heteroaryl ring.

In some embodiments, ring B is an aryl. In some embodiments, ring B isphenyl. In some embodiments, ring B is a heteroaryl ring. In someembodiments, ring B is a monocyclic heteroaryl ring or a bicyclicheteroaryl ring. In some embodiments, ring B is a monocyclic heteroarylring. In some embodiments, ring B is a bicyclic heteroaryl ring. In someembodiments, ring B is selected from phenyl, pyridinyl and thiophenyl.In some embodiments, ring B is selected from pyridinyl and thiophenyl.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8a) and R^(8b) togetherwith the atoms to which they are attached form a substituted orunsubstituted saturated, or partially saturated 3-7 membered spirocycleor heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;or R^(8c) and R^(8d) together with the atoms to which they are attachedform a substituted or unsubstituted saturated, or partially saturated3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatomsselected from S, O and N.

Within this group are compounds having the structure of Formula E-XV-1,Formula E-XV-2, Formula E-XV-3, or Formula E-XV-4:

or Formula E-XVI-1 or Formula E-XVI-2:

wherein R^(A) is H, C₁-C₃alkyl or —C(═O)C₁-C₃alkyl.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8b) and R^(8c) togetherform a bond.

Among the compounds of Formula E-I described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(8d) and R^(8e) togetherform a bond.

Within this group are compounds having the structure of Formula E-XVII-1or Formula E-XVII-2:

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-XVIII:

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of FormulaE-XIX:

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure of Formula E-XX:

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds having the structure Formula E-XXI,or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof:

-   -   wherein,    -   W³ is O, S, or C(R^(8e))(R^(8f));    -   R¹ is H, or C₁-C₆alkyl;    -   X¹ is O, N—R^(A), S, S(O), or S(O)₂;    -   R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₆alkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(2a) and R^(2b) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, and —C(═O)R^(B);    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) are independently selected from H, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   each R⁵ is independently selected from H, C₁-C₃alkyl,        C₁-C₃haloalkyl, C₁-C₃heteroalkyl and        —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   each R⁷ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p is 0, 1 or 2;    -   R^(8a) and R^(8b) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   R^(8e) and R^(8f) are independently selected from H, C₁-C₆alkyl,        and C₁-C₆fluoroalkyl;    -   where each substituted alkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹;        and    -   each R⁹ is independently selected from halogen, —OH, —SH, (C═O),        CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄        fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH,        —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R^(2a), R^(2b) R^(2c), R^(2d), R^(2e), and R^(2f) are        independently selected from H, C₁-C₃alkyl and —C(═O)R^(B); and    -   R^(B) is substituted or unsubstituted C₁-C₆alkyl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl).

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R^(2a), R^(2b) R^(2c),R^(2d), R^(2e) and R^(2f) are independently H or C₁-C₃ alkyl.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R¹ is H or methyl.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R¹ is H.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁵, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷, or        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is a substituted or unsubstituted C₂-C₁₀heterocycloalkyl.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is a substituted or unsubstituted heteroaryl.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, —S(═O)₂NHR⁷, —(C₁-C₃alkyl)-C(═O)NHR⁵, or        —(C₁-C₃alkyl)-S(═O)₂NHR⁷.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁶ is —C(═O)NHR⁷, or —S(═O)₂NHR⁷.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein R⁶ is —C(═O)NHR⁷.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   each R⁷ is independently selected from a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), -(CH₂)_(p)—CH(substituted or unsubstituted        aryl)₂-(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl).

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein,

-   -   R⁷ is independently selected from a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, and        —(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂.

Among the compounds of Formula E described above or below, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is one group of compounds wherein, R⁷ is selected from

Also provided herein are pharmaceutical compositions comprising acompound of Formula E, or pharmaceutically acceptable salt, N-oxide,racemate or stereoisomer thereof, and a pharmaceutically acceptablecarrier.

Also contemplated within the scope of embodiments described herein aredimeric compounds. In one aspect, provided herein are compounds ofFormula F:

wherein Z¹ and Z² are compounds selected from any one of Formula A,Formula B, Formula C, Formula D or Formula E described above or below;and L is a bridge between the compounds such that a compound of FormulaF is a dimeric compound. In some embodiments, L is a bond (e.g., a bondbetween two aryl groups of Z¹ and Z². In some embodiments, L is adisulfide linkage. In some embodiments, L is an ether, amide or esterlinkage. In some embodiments, L is a cycle (e.g., a cyclopropyl ring, apyrrolidine ring, a phenyl ring). In some embodiments, a compound ofFormula F is selected from:

Also contemplated within the scope of embodiments described herein aretrimeric compounds. In one aspect, provided herein are compounds ofFormula G:

wherein Z¹ and Z² and Z³ are compounds selected from any one of FormulaA, Formula B, Formula C, Formula D or Formula E described above orbelow; and L¹ and L² are a bridges between the compounds such that acompound of Formula G is a trimeric compound. In some embodiments, L¹and L² are independently selected from a bond (e.g., a bond between twoaryl groups of Z¹ and Z² or Z³), a disulfide linkage, an ether, amide orester linkage and the like.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

Methods

Provided herein are methods of treating a hyperproliferative disorder inan individual in need thereof comprising administration of atherapeutically effective amount of a compound of any one Formula A,Formula B, Formula C, Formula D, Formula E, Formula F or Formula G, tothe individual in need thereof.

In some of such embodiments, the hyperproliferative disorder is canceror an autoimmune disease.

In some of such embodiments, the autoimmune disease is hemolytic anemia,autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue,chronic fatigue syndrome, Crohn's disease, dermatomyositis,fibromyalgia, graft versus host disease, Grave's disease, Hashimoto'sthyroiditis, idiopathic thrombocytopenia purpura, lichen planus,multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever,rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupuserythematosus, type 1 diabetes, ulcerative colitis, or vitiligo.

Also provided herein are methods of treating cancer in an individual inneed thereof comprising administration of a therapeutically effectiveamount of a compound of any one of Formula A, Formula B, Formula C,Formula D, Formula E, Formula F or Formula G, to the individual in needthereof.

In some embodiments, the cancer is an epithelial cancer, a carcinoma, aneoplasm, a sarcoma, a chondrosarcoma, a blastoma, a cancer of thecentral nervous system, or a haematological cancer. In some embodiments,the cancer is an epithelial cancer or a carcinoma. In some embodiments,the cancer is a neoplasm or a sarcoma or a chondrosarcoma or a blastomaor a cancer of the central nervous system. In some embodiments, thecancer is a haematological cancer.

Also provided herein are methods of treating a disease associated withangiogenesis in an individual in need thereof comprising administrationof a therapeutically effective amount of a compound of any one ofFormula A, Formula B, Formula C, Formula D, Formula E, Formula F orFormula G, to the individual in need thereof.

In some embodiments the disease associated with angiogenesis is maculardegeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy,retinopathy of prematurity, corneal graft rejection, neovascularglaucoma, retrolental fibroplasia, rubeosis, Osler-Webber Syndrome,myocardial angiogenesis, plaque neovascularization, telangiectasia,hemophiliac joints, angiofibroma, wound granulation, intestinaladhesions, atherosclerosis, scleroderma or hypertrophic scarring.

Also provided herein are methods of inhibiting the activity of inhibitorof apoptosis (IAP) proteins in an individual in need thereof comprisingadministration of a therapeutically effective amount of a compound ofany one of Formula A, Formula B, Formula C, Formula D, Formula E,Formula F or Formula G, to the individual in need thereof.

In some embodiments, the IAP protein is XIAP, cIAP-1, cIAP-2, ML-IAP,survivin, NAIP, apollon, or ILP2.

Also provided herein are methods of inducing apoptosis in a cellcomprising contacting the cell with a therapeutically effective amountof a compound of any one of Formula A, Formula B, Formula C, Formula D,Formula E, Formula F or Formula G. In some of such embodiments thecompound of any one of Formula A, Formula B, Formula C, Formula D,Formula E, Formula F or Formula G, binds a XIAP BIR3 domain, thusantagonizing the action of IAPs.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compounds as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein. As a guidethe following synthetic methods may be utilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles and/or nucleophiles to form new functional groups orsubstituents. Table IA entitled “Examples of Covalent Linkages andPrecursors Thereof” lists selected non-limiting examples of covalentlinkages and precursor functional groups which yield the covalentlinkages. Table IA may be used as guidance toward the variety ofelectrophiles and nucleophiles combinations available that providecovalent linkages. Precursor functional groups are shown aselectrophilic groups and nucleophilic groups.

TABLE I Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Alkyl amines alkylhalides amines/anilines Esters alkyl halides carboxylic acids Thioethersalkyl halides Thiols Ethers alkyl halides alcohols/phenols Thioethersalkyl sulfonates Thiols Esters Anhydrides alcohols/phenols CarboxamidesAnhydrides amines/anilines Thiophenols aryl halides Thiols Aryl aminesaryl halides Amines Thioethers Azindines Thiols Carboxamides carboxylicacids amines/anilines Esters carboxylic acids Alcohols hydrazinesHydrazides carboxylic acids N-acylureas or Anhydrides carbodiimidescarboxylic acids Esters diazoalkanes carboxylic acids ThioethersEpoxides Thiols Thioethers haloacetamides Thiols Ureas Isocyanatesamines/anilines Urethanes Isocyanates alcohols/phenols Thioureasisothiocyanates amines/anilines Thioethers Maleimides Thiols Alkylamines sulfonate esters amines/anilines hioethers sulfonate estersThiols Sulfonamides sulfonyl halides amines/anilines Sulfonate esterssulfonyl halides phenols/alcoholsUse of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups can be removed by acid, base, reducing conditions(such as, for example, hydrogenolysis), and/or oxidative conditions.Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilylare acid labile and may be used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. Carboxylic acid and hydroxy reactive moieties may be blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Synthesis of Compounds of Formula A

In some embodiments, a compound of Formula A-I is synthesized as shownbelow in Scheme 1 and in the Chemistry Examples section:

Starting with a compound of Formula 1-1, a four component Ugi reactionprovides a compound of Formula 1-2, which is then cyclized anddeprotected to provide a compound of Formula A-I.

In a further embodiment, compounds of Formula A-I are synthesizedstarting with compound 1-6 as shown in Scheme 2 below:

Table 1-1 shows data for certain compounds of Formula A-I.

TABLE 1-1 XIAP XIAP Yield BIR1/2 BIR3 Product R^(2a) R² (2 steps) K_(i)(μM) K_(i) (μM) 7a H

30% C B 7b H

69% C B 7c H

67% C A 7d Me

 79%* C A 7e Me

63% C B 7f Me

46% C B KEY: A = ≦25 micromolar; B >25 and ≦50 micromolar; C >50micromolar

Other compounds that are useful for the Ugi reaction shown above orbelow include and are not limited to:

Synthesis of Compounds of Formula B

In some embodiments, a compound of Formula B-I is synthesized as shownbelow in Scheme 3:

Starting with a compound of Formula 2-1, a four component Ugi reactionprovides a compound of Formula 2-2. X is a protected thiol, or protectedhydroxyl, or N—R^(A) as described herein. The compound of Formula 2-2 iscyclized and a reaction with a protected alanine provides a compound ofFormula B-I as a mixture of diastereomers. The mixture of diastereomersis separated by silica gel chromatography to provide a compound ofFormula B-I having the structure 2-4. Where Y is S, the sulfur atom isoptionally oxidized.

Table 2-1 and below and FIG. 1 show certain data for compounds ofFormula B:

TABLE 2-1 XIAP XIAP ML- BIR1/2 BIR3 IAP Prod- Yield K_(i) K_(i) K_(i)uct Y R¹ (4 steps) (μM) (μM) (μM) 16a O

44% C A A 16b O

36% A A — 16c S

47% C A A 16d O

ND C A A 16e O

41% C B — KEY: A = ≦25 micromolar; B >25 and ≦50 micromolar; C >50micromolar

In an alternative embodiment, compounds of Formula B-XV are synthesizedaccording to Scheme 4 shown below.

Starting with a compound of Formula 2-1, a four component Ugi reactioncomprising a compound of Formula 3-1 followed by cylization and areaction with a protected alanine as shown in Scheme 3 provides acompound of Formula B-XV. Table 2-2 below shows certain data forcompounds of Formula B-XV:

TABLE 2-2 XIAP XIAP Yield BIR1/2 BIR3 ML-IAP Product Structure (4 steps)K_(i) (μM) K_(i) (μM) K_(i) (μM) 17a

43% C A A 17b

49% A A A 17c

60% A A A KEY: A = ≦25 micromolar; B >25 and ≦50 micromolar; C >50micromolar

It will be understood that the reactions shown in Schemes 1-4 above areillustrative and are also applicable to synthesis of compounds ofFormula C, Formula D and Formula E, and such disclosure is contemplatedwithin the scope of embodiments described herein. Synthesis of compoundsof Formula C, Formula D and Formula E is shown in further detail in theChemistry Examples section.

Administration and Pharmaceutical Composition

In general, the compounds of this invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Therapeuticallyeffective amounts of compounds of Formula A, Formula B, Formula C,Formula D, Formula E, Formula F or Formula G may range from about 0.01to about 500 mg per kg patient body weight per day, which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 toabout 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about0.1 to about 50 mg/kg per day. Within this range the dosage can be about0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg perday. For oral administration, the compositions are preferably providedin the form of tablets containing about 1.0 to about 1000 milligrams ofthe active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50,75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000milligrams of the active ingredient. The actual amount of the compoundof this invention, i.e., the active ingredient, will depend uponnumerous factors such as the severity of the disease to be treated, theage and relative health of the subject, the potency of the compoundbeing utilized, the route and form of administration, and other factors.

In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., intranasal, suppository, intrapulmonaary), or parenteral(e.g., intramuscular, intravenous, intrathecal, or intraperitoneal)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of in general, a compound of Formula A,Formula B, Formula C, Formula D, Formula E, Formula F or Formula G incombination with at least one pharmaceutically acceptable excipient.Acceptable excipients are non-toxic, aid administration, and do notadversely affect the therapeutic benefit of the compound of Formula A,Formula B, Formula C, Formula D, Formula E, Formula F or Formula G. Suchexcipient may be any solid, liquid, semi-solid or, in the case of anaerosol composition, gaseous excipient that is generally available toone of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 20th ed., 2000).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt% of a compound of Formula A, Formula B, Formula C, Formula D, FormulaE, Formula F or Formula G based on the total formulation, with thebalance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment of diseases or conditions forwhich compounds of the present invention or the other drugs may haveutility, where the combination of the drugs together are safer or moreeffective than either drug alone. Such other drug(s) may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of the present invention is preferred. However, the combinationtherapy may also include therapies in which the compound of the presentinvention and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the compounds ofthe present invention and the other active ingredients may be used inlower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present inventionalso include those that contain one or more other active ingredients, inaddition to a compound of the present invention.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventionalso include those that also contain one or more other activeingredients, in addition to a compound of the present invention. Theweight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of a compound described herein isoptionally given continuously; alternatively, the dose of drug beingadministered is temporarily reduced or temporarily suspended for acertain length of time (i.e., a “drug holiday”). The length of the drugholiday optionally varies between 2 days and 1 year, including byway ofexample only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days,120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days,320 days, 350 days, or 365 days. The dose reduction during a drugholiday includes from 10%-100%, including, by way of example only, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, is reduced, as a function of thesymptoms, to a level at which the improved disease, disorder orcondition is retained. In some embodiments, patients requireintermittent treatment on a long-term basis upon any recurrence ofsymptoms.

Combination Therapy

In some cases, a compound described herein is administered incombination with a second anti-cancer agent. Examples of anti-canceragents for use in combination with a compound of Formula A, Formula B,Formula C, Formula D, Formula E, Formula F or Formula G includeinhibitors of mitogen-activated protein kinase signaling, e.g., U0126,PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; andantibodies (e.g., rituxan).

Other anti-cancer agents that can be employed in combination with acompound of Formula A, Formula B, Formula C, Formula D, Formula E,Formula F or Formula G include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine;gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;ifosfamide; ilmofosine; interleukin II (including recombinantinterleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b;interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferongamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride.

Other anti-cancer agents that can be employed in combination with acompound of Formula A, Formula B, Formula C, Formula D, Formula E,Formula F or Formula G include: 20-epi-1, 25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; fmasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; R₁₁ retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived 1; sense oligonucleotides; signaltransduction inhibitors; signal transduction modulators; single chainantigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stem cell inhibitor; stem-cell division inhibitors;stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactiveintestinal peptide antagonist; suradista; suramin; swainsonine;synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide;tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;telomerase inhibitors; temoporfin; temozolomide; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; totipotent stem cell factor; translation inhibitors;tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin;tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBCinhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor;urokinase receptor antagonists; vapreotide; variolin B; vector system,erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin;zilascorb; and zinostatin stimalamer.

Yet other anticancer agents that can be employed in combination with acompound of Formula A, Formula B, Formula C, Formula D, Formula E,Formula F or Formula G include alkylating agents, antimetabolites,natural products, or hormones, e.g., nitrogen mustards (e.g.,mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with a compound ofFormula A, Formula B, Formula C, Formula D, Formula E, Formula F orFormula G include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha).

Examples of alkylating agents that can be employed in combination acompound of Formula A, Formula B, Formula C, Formula D, Formula E,Formula F or Formula G include, but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination a compound ofFormula A, Formula B, Formula C, Formula D, Formula E, Formula F orFormula G include, but are not limited to, adrenocorticosteroids (e.g.,prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrolacetate, medroxyprogesterone acetate), estrogens (e.g.,diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen),androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen(e.g., flutamide), gonadotropin releasing hormone analog (e.g.,leuprolide). Other agents that can be used in the methods andcompositions described herein for the treatment or prevention of cancerinclude platinum coordination complexes (e.g., cisplatin, carboblatin),anthracenedione (e.g., mitoxantrone), substituted urea (e.g.,hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with an irreversible EGFR tyrosine kinase inhibitor compoundinclude without limitation the following marketed drugs and drugs indevelopment: Erbulozole (also known as R-55104), Dolastatin 10 (alsoknown as DLS-10 and NSC-376128), Mivobulin isethionate (also known asCI-980), Vincristine, NSC-639829, Discodermolide (also known asNVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such asSpongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (also known as LU-103793 andNSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D(also referred to as KOS-862, dEpoB, and desoxyepothilone B), EpothiloneE, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705),21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF),26-fluoroepothilone), Auristatin PE (also known as NSC-654663),Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known asLS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477(Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristinesulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known asWS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy ofSciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651),SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97(Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739(Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto,also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known asNSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 andTI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261), H10 (Kansas State University), H16 (Kansas State University),Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker HughesInstitute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute),SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

In some cases, a compound described herein (e.g., a compound of FormulaA, Formula B, Formula C, Formula D, Formula E, Formula F or Formula G)is administered in combination with TNF-alpha and/or TNF-relatedapoptosis-inducing ligand (TRAIL). TRAIL shows homology to other membersof the TNF-alpha family of proteins. In some cases, a compound describedherein (e.g., a compound of Formula A, Formula B, Formula C, Formula D,Formula E, Formula F or Formula G) is administered in combination with aTNF-alpha modulator and/or a TNF-alpha analogue (e.g., lenalidomide,revlimid, CC-5013; CC-4047, ACTIMID. Tthalidomide and the like). In somecases, a compound described herein (e.g., a compound of Formula A,Formula B, Formula C, Formula D, Formula E, Formula F or Formula G) isadministered in combination with an adjuvant, hormone therapy,immunotherapy or any combination thereof.

Methods of Use

Disclosed herein, in certain embodiments, are methods of inhibiting theactivity of an inhibitor of apoptosis (IAP) protein in an individual inneed thereof comprising administering a therapeutically effective amountof a compound disclosed herein to the individual. In some embodiments,the IAP protein is XIAP, cIAP-1, cIAP-2, ML-IAP, survivin, NAIP,apollon, ILP2, or any combinations thereof.

In some embodiments, inhibiting the activity of an IAP protein inducesapoptosis in a plurality of cells. In some embodiments, the cells arecancerous cells. In some embodiments, the cancer is a sarcoma,carcinoma, blastoma, myeloma, leukemia, lymphoma, or combinationsthereof. In some embodiments, the cancer is a skin cancer, lung cancer,breast cancer, prostate cancer, colorectal cancer, cervical cancer,uterine cancer, pancreatic cancer, liver cancer, or any combinationsthereof. In some embodiments, the cancer is acute myelogenous leukemia(AML). In some embodiments, the cancer is renal cell carcinoma. In someembodiments, the cancer is ovarian cancer. In some embodiments, thecancer is prostate cancer. In some embodiments, the cancer is renal cellcarcinoma. In some embodiments, the cancer is glioblastoma. In someembodiments, the cancer is gastric carcinoma. In some embodiments, thecancer is esophageal squamous cell carcinoma. In some embodiments, thecancer is a lung cancer. In some embodiments, the lung cancer isnon-small cell lung carcinoma or small cell lung cancer. In someembodiments, the cancer is multiple myeloma. In some embodiments, thecancer is pancreatic cancer. In some embodiments, the cancer is breastcancer.

In some embodiments, inhibiting the activity of an IAP protein treats ahyperproliferative disorder. In some embodiments, the hyperproliferativedisorder is a cancer or an autoimmune disease. In some embodiments, theautoimmune disease is hemolytic anemia, autoimmune hepatitis, Berger'sdisease or IgA nephropathy, celiac sprue, chronic fatigue syndrome,Crohn's disease, dermatomyositis, fibromyalgia, graft versus hostdisease, Grave's disease, Hashimoto's thyroiditis, idiopathicthrombocytopenia purpura, lichen planus, multiple sclerosis, myastheniagravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma,Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes,ulcerative colitis, or vitiligo. In some embodiments, the cancer is asarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, orcombinations thereof. In some embodiments, the cancer is a skin cancer,lung cancer, breast cancer, prostate cancer, colorectal cancer, cervicalcancer, uterine cancer, pancreatic cancer, liver cancer, or anycombinations thereof. In some embodiments, the cancer is acutemyelogenous leukemia (AML). In some embodiments, the cancer is renalcell carcinoma. In some embodiments, the cancer is ovarian cancer. Insome embodiments, the cancer is prostate cancer. In some embodiments,the cancer is renal cell carcinoma. In some embodiments, the cancer isglioblastoma. In some embodiments, the cancer is gastric carcinoma. Insome embodiments, the cancer is esophageal squamous cell carcinoma. Insome embodiments, the cancer is a lung cancer. In some embodiments, thelung cancer is non-small cell lung carcinoma or small cell lung cancer.In some embodiments, the cancer is multiple myeloma. In someembodiments, the cancer is pancreatic cancer. In some embodiments, thecancer is breast cancer.

Disclosed herein, in certain embodiments, are methods of treating acancer in an individual in need thereof comprising administering atherapeutically effective amount of a compound disclosed herein to theindividual. In some embodiments, the cancer is a sarcoma, carcinoma,blastoma, myeloma, leukemia, lymphoma, or combinations thereof. In someembodiments, the cancer is a skin cancer, lung cancer, breast cancer,prostate cancer, colorectal cancer, cervical cancer, uterine cancer,pancreatic cancer, liver cancer, or any combinations thereof. In someembodiments, the cancer is acute myelogenous leukemia (AML). In someembodiments, the cancer is renal cell carcinoma. In some embodiments,the cancer is ovarian cancer. In some embodiments, the cancer isprostate cancer. In some embodiments, the cancer is renal cellcarcinoma. In some embodiments, the cancer is glioblastoma. In someembodiments, the cancer is gastric carcinoma. In some embodiments, thecancer is esophageal squamous cell carcinoma. In some embodiments, thecancer is a lung cancer. In some embodiments, the lung cancer isnon-small cell lung carcinoma or small cell lung cancer. In someembodiments, the cancer is multiple myeloma. In some embodiments, thecancer is pancreatic cancer. In some embodiments, the cancer is breastcancer.

Disclosed herein, in certain embodiments, are methods of treating adisease associated with unwanted angiogenesis in an individual in needthereof comprising administering a therapeutically effective amount of acompound disclosed herein to the individual. In some embodiments, thedisease associated with unwanted angiogenesis is macular degeneration,rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy ofprematurity, corneal graft rejection, neovascular glaucoma, retrolentalfibroplasia, rubeosis, Osler-Webber Syndrome, myocardial angiogenesis,plaque neovascularization, telangiectasia, hemophiliac joints,angiofibroma, wound granulation, intestinal adhesions, atherosclerosis,scleroderma or hypertrophic scarring. In some embodiments, the diseaseassociated with unwanted angiogenesis is a cancer. In some embodiments,the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia,lymphoma, or combinations thereof. In some embodiments, the cancer is askin cancer, lung cancer, breast cancer, prostate cancer, colorectalcancer, cervical cancer, uterine cancer, pancreatic cancer, livercancer, or any combinations thereof. In some embodiments, the cancer isacute myelogenous leukemia (AML). In some embodiments, the cancer isrenal cell carcinoma. In some embodiments, the cancer is ovarian cancer.In some embodiments, the cancer is prostate cancer. In some embodiments,the cancer is renal cell carcinoma. In some embodiments, the cancer isglioblastoma. In some embodiments, the cancer is gastric carcinoma. Insome embodiments, the cancer is esophageal squamous cell carcinoma. Insome embodiments, the cancer is a lung cancer. In some embodiments, thelung cancer is non-small cell lung carcinoma or small cell lung cancer.In some embodiments, the cancer is multiple myeloma. In someembodiments, the cancer is pancreatic cancer. In some embodiments, thecancer is breast cancer.

CHEMISTRY EXAMPLES

The following examples are intended to illustrate but not limit thedisclosed embodiments. All solvents were used as purchased fromcommercial sources or dried over 4 Å molecular sieves prior to use inthe case of moisture sensitive reactions. Reactions conducted undermicrowave irradiation were performed in a CEM Discover microwave reactorusing either CEM 10 mL reaction vessels or a ChemGlass heavy wallpressure vessel (100 mL, 38 mm×190 mm). Reaction progress was monitoredby reverse-phase HPLC and/or thin-layer chromatography (TLC). Highresolution mass spectrometry was performed using ESI-TOFMS, EI-MS(reference: perfluorokerosene) and APCI-MS. TLC was performed usingsilica gel 60 F254 pre-coated plates (0.25 mm). Flash chromatography wasperformed using silica gel (32-63 μm particle size) or aluminum oxide(activated, basic, ˜150 mesh size). All products were purified tohomogeneity by TLC analysis (single spot, unless stated otherwise),using a UV lamp and/or iodine and/or CAM or basic KMnO₄ for detectionpurposes. NMR spectra were recorded on 400 MHz and 500 MHz spectrometersat ambient temperature. ¹H and ¹³C NMR chemical shifts are reported as δusing residual solvent as an internal standard; CDCl₃: 7.26, 77.16 ppm;CD₃OD: 3.31, 49.00 ppm; DMSO-d₆: 2.50, 39.52 ppm, CD₃CN: 1.94 (¹H), 1.32(¹³C) ppm. Abbreviations used: alanine (Ala), 1-hydroxybenzotriazole(HOBT), N-methylmorpholine (NMM),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC), palladium oncarbon (Pd-C), dichloromethane (DCM), diethyl ether (Et₂O), ethylacetate (EtOAc), 2,2,2-trifluoroethanol (TFE), methanol (MeOH),homoserine (HSer), tetrahydrofuran (THF), trifluoroacetic acid (TFA),diisobutylaluminum hydride (DIBAL).

Example 1 Preparation of (S)-benzyl3-(benzyloxy)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)propanoate

To a solution of the serine derivative (1.74 g, 3.80 mmol, 1.0 equiv),Boc-N-Me-Ala-OH (773 mg, 3.80 mmol, 1.0 equiv), HOBT.xH₂O (641 mg, 4.18mmol, 1.1 equiv) and NMM (1.25 mL, 11.4 mmol, 3 equiv) in THF (45 mL) at0° C. was added EDC.HCl (766 mg, 3.99 mmol, 1.05 equiv). After 30 minthe cold bath was removed. The solution stirred for 14 h and then wasquenched with saturated aqueous NaHCO₃ (50 mL), extracted with ethylacetate (2×40 mL), dried over sodium sulfate and then concentrated invacuo. The resultant oil was purified by flash chromatography on silicagel (5:1→4:1→3:1 hexanes/EtOAc) to yield the product (1.70 g, 95%).R_(f)=0.20 (5:1 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 7.34-7.27 (m,8H), 7.19 (dd, 2H, J=2.0, 8.0 Hz), 5.18 (q, 2H, J=12.0 Hz), 4.79-4.74(m, 1H), 4.45 (q, 2H, J=12.0 Hz), 3.89 (dd, 1H, J=3.2, 9.6 Hz), 3.66(dd, 1H, J=3.2, 9.6 Hz), 2.75 (s, 3H), 1.45 (s, 9H), 1.34 (t, 3H, J=7.2Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 171.6, 170.0, 137.5, 135.4, 128.7,128.5, 128.5, 128.3, 127.9, 127.7, 73.4, 69.8, 67.4, 52.9, 30.0, 28.4,13.9; HRMS calcd for C₂₆H₃₄N₂O₆Na: 493.23091. found 493.23211.

Example 2 Preparation of(S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-hydroxypropanoicacid

To a solution of benzyl ester (1.70 g, 3.61 mmol, 1.0 equiv) in methanol(25 mL) was added 10 wt % Pd-C (100 mg). A balloon of H₂ was applied for16 h, then the mixture was filtered through Celite with DCM andconcentrated in vacuo. The resultant oil was purified by flashchromatography on silica gel (1:1 hexanes/EtOAc→100% DCM→5% MeOH/DCM) toyield the product (591 mg, 57%). ¹H NMR (400 MHz, CD₃OD) δ: 4.41 (t, 1H,J=3.6 Hz), 3.91 (dd, 1H, J=4.4, 10.8 Hz), 3.83 (dd, 1H, J=4.0, 11.2 Hz),3.35-3.34 (m, 1H), 2.86 (s, 3H), 1.47 (s, 9H), 1.38 (d, 3H, J=6.8 Hz);¹³C NMR (100 MHz, CD₃CN) δ: 207.9, 173.1, 172.4, 81.0, 62.6, 55.4, 30.9,28.5. HRMS calcd for C₁₂H₂₂N₂O₆Na: 313.1370. found 313.1371.

Example 3 Preparation of (2S,3R)-benzyl3-(benzyloxy)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)butanoate

Same procedure as Example 1 using threonine derivative (4.65 g, 11.9mmol, 1.0 equiv), Boc-N-Me-Ala-OH (2.43 g, 11.9 mmol, 1.0 equiv),HOBT.xH₂O (2.19 g, 14.3 mmol, 1.1 equiv), NMM (3.94 mL, 35.8 mmol, 3equiv) and EDC.HCl (2.75 g, 14.3 mmol, 1.05 equiv) in THF (100 mL). Theresultant oil was purified by flash chromatography on silica gel(5:1→4:1→2:1 hexanes/EtOAc) to yield the product (3.32 g, 57%).R_(f)=0.26 (5:1 hexanes/ethyl acetate). ¹H NMR (400 MHz, CDCl₃) δ:7.31-7.25 (m, 8H), 7.17-7.15 (m, 2H), 5.14 (d, 1H, J=6.0 Hz), 5.06 (d,1H, J=6.0 Hz), 4.67 (dd, 1H, J=2.4, 9.2 Hz), 4.48 (d, 1H, J=12.0 Hz),4.27 (d, 1H, J=12.0 Hz), 4.15 (qd, 1H, J=2.0, 6.0 Hz), 2.79 (s, 3H),1.60 (s, 1H), 1.42 (s, 9H), 1.35 (d, 3H, J=7.2 Hz), 1.16 (d, 3H, 6.4Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 172.2, 170.4, 135.5, 128.7, 128.7,128.5, 128.5, 128.5, 128.4, 127.8, 127.8, 74.3, 70.9, 67.3, 56.8, 28.4,16.4. HRMS calcd for C₂₇H₃₆N₂O₆Na: 507.2466. found 507.2468.

Example 4 Preparation of(2S,3R)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-hydroxybutanoicacid

Same procedure as Example 2 using benzyl ester (3.306 g, 6.82 mmol, 1.0equiv) and 10 wt % Pd-C (150 mg) in methanol (50 mL). The resultant oilwas sufficiently pure as a crude product (2.01 g, 97%). ¹H NMR (400 MHz,CD₃OD) δ: 7.44 (bs, 1H), 4.70 (bs, 1H), 4.40-4.36 (m, 1H), 4.33 (dd, 1H,J=2.8, 6.4 Hz), 2.87 (s, 3H), 1.48 (s, 9H), 1.39 (d, 3H, J=7.2 Hz), 1.18(d, 3H, J=6.4 Hz); ¹³C NMR (100 MHz, CD₃OD) δ: 174.7, 173.7, 157.5,81.9, 68.2, 59.0, 55.7, 30.9, 28.6, 20.7, 14.9. HRMS calcd forC₁₃H₂₄N₂O₆Na: 327.15266. found 327.15236.

Example 5 4,4-Dimethoxybutanal

To a solution of nitrile (1.2 g, 9.29 mmol, 1.0 equiv) in DCM (75 mL) at−78° C. under N₂ was added 1.1 M DIBAL in cyclohexane (23.23 mL, 10.2mmol, 1.1 equiv). After 3 h at −78° C., the mixture was slowly warmed tor.t. and quenched with sat. aq. NH₄Cl (25 mL) and Rochelle salt (25 mL).Reaction progress was monitored by TLC (vanillin stain). After stirringfor 1 h, the mixture was extracted with DCM (3×20 mL). The organics werethen washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to yield a colorless, relatively volatile liquidproduct (1.14 g, 93%) which was sufficiently pure to use without furtherpurification. The analytical data match those previously reported:Griesbaum, K.; Jung, I. C.; Mertens, H. J. Org. Chem. 1990, 55, 6024.

Example 6 4,4-Dimethoxy-2,2-dimethylbutanenitrile

To a solution of diisopropylamine (4.77 mL, 34.1 mmol, 2.2 equiv) in THF(50 mL) at −10° C. under N₂ was added 1.5 M n-BuLi in hexanes (22.7 mL,34.1 mmol, 2.2 equiv). After 30 min the mixture was cooled to −78° C.and a solution of nitrile (2.0 g, 15.5 mmol, 1.0 equiv) in THF (10 mL)was added. After 1 h iodomethane (2.12 mL, 34.1 mmol, 2.2 equiv) wasadded. The mixture was slowly warmed to 0° C. and kept there for 14 h,at which time it was quenched with sat. aq. NH₄Cl (40 mL) and extractedwith EtOAc (3×20 mL). The organics were dried over Na₂SO₄, filtered andconcentrated in vacuo. The resultant oil was purified by flashchromatography on silica gel (5:1→3:1 hexanes/EtOAc) to yield theproduct (2.105 g, 87%) as a yellow oil. R_(f)=0.49 (3:1 hexanes/EtOAc).¹H NMR (400 MHz, CDCl₃) δ: 4.60 (t, 1H, J=5.6 Hz), 3.37 (s, 6H), 1.83(d, 2H, J=4.4 Hz), 1.39 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 124.7,102.4, 53.3, 43.0, 30.0, 27.5

Example 7 Preparation of 4,4-dimethoxy-2,2-dimethylbutanal

Same procedure as Example 5 using the nitrile derivative (500 mg, 3.18mmol, 1.0 equiv) in DCM (25 mL) and 1.1 M DIBAL in cyclohexane (3.18 mL,10.2 mmol, 1.1 equiv). The resultant oil was purified by flashchromatography on silica gel (9:1 hexanes/EtOAc) to yield the product(232 mg, 46%) as a colorless, relatively volatile oil. R_(f)=0.39 (7:1hexanes/EtOAc).

Example 8 Preparation of 2-(diethoxymethyl)benzaldehyde

To a solution of aryl bromide (1.94 g, 7.49 mmol, 1.0 equiv) in THF (20mL) at −78° C. under N₂ was added 1.5 M n-BuLi in hexanes (7.49 mL, 11.2mmol, 1.5 equiv). After 30 min DMF (869 μL, 11.2 mmol, 1.5 equiv) wasadded. The mixture was slowly warmed to r.t. over 4 h, at which time itwas quenched with sat. aq. NH₄Cl (40 mL) and extracted with EtOAc (3×20mL). The organics were dried over Na₂SO₄, filtered and concentrated invacuo. The resultant oil was purified by flash chromatography on silicagel (95:4:1 hexanes/EtOAc/Et₃N) to yield the product (2.105 g, 87%) as ayellow oil. R_(f)=0.46 (3:1 hexanes/EtOAc). The analytical data matchthose previously reported: Ueda, M.; Kawai, S.; Hayashi, M.; Naito, T.;Miyata., O. J. Org. Chem. 2010, 75, 914.

Example 9 N-(Naphthalen-1-yl)formamide

To a mixture of 1-naphthylamine (6.0 g, 41.9 mmol, 1.0 equiv) and ethylformate (6.74 mL, 83.8 mmol, 2 equiv) in THF (200 mL) was added 1 MLHMDS in THF (75.4 mL, 75.4 mmol, 1.8 equiv). The mixture was heated to85° C. for 14 h and then concentrated. The resulting solid was filteredand rinsed with hexanes to yield the product. The filtrate wasconcentrated and the filtration procedure was repeated for a secondbatch of product to yield overall the product (3.05 g, 64%) as a brownsolid and a 2:1 mixture of rotational isomers. R_(f)=0.10 (5:1hexanes/ethyl acetate). ¹H NMR (400 MHz, CDCl₃) δ: 8.65-8.61 (m, 2H),8.45 (bs, 1H), 8.04-7.99 (m, 2H), 7.92-7.85 (m, 2H), 7.80 (d, 1H, J=8.4Hz), 7.73 (d, 1H, J=8.0 Hz), 7.63-7.51 (m, 3H), 7.50-7.44 (m, 2H), 7.32(d, 1H, J=7.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 164.1, 159.7, 134.4,134.2, 132.2, 131.1, 129.0, 128.7, 127.9, 127.2, 127.2, 127.2, 127.0,126.7, 126.4, 126.3, 125.9, 125.7, 121.4, 121.0, 120.5, 119.3. HRMScalcd for C₁₁H₉NO: 171.0679. found 171.0681.

Example 10 Preparation of 1-isocyanonaphthalene

To a solution of formamide derivative (1.048 g, 6.12 mmol, 1.0 equiv) inDCM (20 mL) at 0° C. was added Et₃N (4.33 mL, 31.2 mmol, 5.1 equiv)followed by phosphorus oxychloride (841 μL, 9.18 mmol, 1.5 equiv). Themixture was warmed to 23° C. and stirred for 2 h, at which time it waspoured into a mixture of saturated NaHCO₃ (40 mL) and 1 M NaOH (20 mL)and extracted with DCM (3×20 mL). The organics were dried over Na₂SO₄,filtered and concentrated in vacuo. The resultant oil was purified byflash chromatography on silica gel (1:1 hexanes/DCM) to yield theproduct (740 mg, 79%) as a brown oil which was stored at 0° C.R_(f)=0.72 (3:1 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 8.19 (d, 1H,J=8.4 Hz), 7.90 (d, 2H, J=8.0 Hz), 7.68 (t, 1H, J=7.6 Hz), 7.61 (t, 2H,J=7.2 Hz), 7.45 (td, 1H, J=2.4, 8.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ:167.3, 133.7, 129.9, 128.5, 128.2, 128.1, 127.6, 125.1, 124.7, 123.1.HRMS calcd for C₁₁H₈N: 154.06513. found 154.06671.

Example 11 Preparation of N-benzhydrylformamide

A mixture of benzhydrylamine (4.0 g, 21.8 mmol, 1.0 equiv) and ethylformate (2.0 mL, 24.9 mmol, 1.14 equiv) was heated to 75° C. for 14 h.Ethyl acetate was added and the mixture was triturated by sonication,then filtered and rinsed with Et₂O to yield the product (3.24 g, 70%) asa white solid. The compound exists as a mixture of rotational isomers.R_(f)=0.29 (3:1 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 8.15 (s, 1H),7.34-7.19 (m, 10H), 6.69 (d, 1H, J=6.0 Hz), 6.27 (d, 1H, J=8.4 Hz); ¹³CNMR (100 MHz, CDCl₃) δ: 160.4, 141.0, 128.8, 127.7, 127.5, 55.7. HRMScalcd for C₁₄H₁₄NO: 212.10699. found 212.100748.

Example 12 Preparation of (isocyanomethylene)dibenzene

To a solution of formamide derivative (1.727 g, 8.17 mmol, 1.0 equiv) inDCM (35 mL) at 0° C. was added Et₃N (5.79 mL, 41.7 mmol, 5.1 equiv)followed by phosphorus oxychloride (1.12 mL, 12.3 mmol, 1.5 equiv). Themixture was warmed to 23° C. and stirred for 18 h, at which time it waspoured into a mixture of saturated NaHCO₃ (50 mL) and 1 M NaOH (20 mL)and extracted with DCM (3×30 mL). The organics were dried over Na₂SO₄,filtered and concentrated in vacuo. The resultant oil was purified byflash chromatography on silica gel (DCM→5:1 DCM/EtOAc) to yield theproduct (1.467 g, 93%) as an orange solid which was stored at 0° C.R_(f)=0.73 (7:1 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.33 (m,10H), 5.92 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.5, 137.7, 129.1,128.6, 126.7, 77.2, 62.1. HRMS calcd for C₁₄H₁₁NNa: 216.07837. found216.07971.

Example 13 Preparation of(R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)formamide

A mixture of (R)-(−)-1,2,3,4-tetrahydro-1-naphthylamine (10.0 g, 67.9mmol, 1 equiv) and ethyl formate (6.23 mL, 77.4 mmol, 1.14 equiv) washeated to 80° C. for 14 h. Hexanes was added and the mixture wastriturated by sonication, then filtered and rinsed with hexanes to yieldthe product (7.44 g, 63%) as a tan solid. R_(f)=0.22 (3:1hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 8.23 (s, 1H), 7.29-7.25 (m,1H), 7.23-7.16 (m, 2H), 7.13-7.08 (m, 1H), 5.82 (bs, 1H), 5.28 (dd, 1H,J=5.2, 14.0 Hz), 2.85-2.73 (m, 2H), 2.15-2.03 (m, 1H), 1.88-1.81 (m,3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.5, 137.7, 136.1, 129.4, 128.8,127.6, 126.5, 46.4, 30.3, 29.3, 20.0. HRMS calcd for C₁₁H₁₃NONa:198.0889. found 198.0890.

Example 14 Preparation of (R)-1-isocyano-1,2,3,4-tetrahydronaphthalene

To a solution of formamide derivative (2.85 g, 16.3 mmol, 1.0 equiv) inDCM (40 mL) at 0° C. was added Et₃N (11.51 mL, 82.9 mmol, 5.1 equiv)followed by phosphorus oxychloride (2.23 mL, 24.4 mmol, 1.5 equiv). Themixture was warmed to 23° C. and stirred for 2 h, at which time it waspoured into saturated NaHCO₃ (200 mL) and extracted with DCM (2×100 mL).The organics were dried over Na₂SO₄, filtered and concentrated in vacuo.The resultant oil was purified by flash chromatography on silica gel(3:1→1:1 hexanes/DCM) to yield the product (1.76 g, 69%) as a brown oilwhich was stored at 0° C. R_(f)=0.59 (5:1 hexanes/EtOAc). ¹H NMR (400MHz, CDCl₃) δ: 7.45-7.43 (m, 1H), 7.26-7.23 (m, 2H), 7.14-7.11 (m, 1H),4.83 (app. s, 1H), 2.92-2.84 (m, 1H), 2.80-2.72 (m, 1H), 2.18-2.12 (m,2H), 2.11-2.01 (m, 1H), 1.87-1.78 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ:155.2, 136.5, 132.1, 129.5, 128.6, 128.6, 126.7, 52.6, 30.7, 28.6, 19.4.HRMS calcd for C₁₁H₁₂N: 158.0964. found 158.0966.

Example 15 Preparation of 1-(2,2-dimethoxyethyl)-2-isocyanobenzene

The isocyanide was prepared according to the established literatureprocedure; see Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett.2007, 9, 3631.

Example 16 General synthetic scheme for the preparation of6,5-heterobicyclic compounds described below

Example 17 Preparation of(3S,8aS)—N-benzyl-3-((S)-2-(methylamino)propanamido)-4-oxohexahydro-2H-pyrrolo[2,1-b][1,3]oxazine-6-carboxamide

A mixture of carboxylic acid (93 mg, 0.320 mmol, 1.0 equiv), aldehyde(44 mg, 0.336 mmol, 1.05 equiv), benzyl isocyanide (38 mg, 0.320 mmol,1.0 equiv) and 7 M ammonia in MeOH (92 μL, 0.641 mmol, 2.0 equiv) in TFE(3 mL) was stirred under microwave irradiation at a set temperature of80° C. for 20 min. The mixture was then transferred to a round bottomflask and concentrated in vacuo, then 1 M NaOH (15 mL) was added and themixture was extracted with DCM (3×7 mL). The organics were dried overNa₂SO₄, filtered and concentrated in vacuo. The resultant oil wascombined with TFA (147 μL, 1.92 mmol, 6 equiv) in DCM (5 mL) and stirredat 23° C. for 14 h. The mixture was concentrated in vacuo and purifiedby flash chromatography on basic alumina (3:1 hexanes/EtOAc→DCM→7%MeOH/DCM) to yield the product as a 1:1 diastereomixture of the freebase (36 mg, 30% over 2 steps). Some of the material was furtherpurified by preparative scale HPLC for use in biological assays. ¹H NMR(400 MHz, CD₃OD) δ: 8.51 (bs, 1H), 7.33-7.28 (m, 8H), 7.26-7.21 (m, 2H),5.23 (t, 1H, J=5.2 Hz), 5.16 (dd, 1H, J=5.2, 8.4 Hz), 4.68 (dd, 1H,J=3.2, 6.4 Hz), 4.61-4.56 (m, 2H), 4.48 (d, 1H, J=15.2 Hz), 4.42-4.33(m, 4H), 4.28 (dd, 1H, J=6.4, 11.6 Hz), 4.24 (dd, 1H, J=6.0, 11.6 Hz),4.01 (dd, 1H, J=3.2, 11.6 Hz), 3.92 (dd, 1H, J=3.2, 11.6 Hz), 3.69 (q,2H, J=6.8 Hz), 2.61 (s, 3H), 2.60 (s, 3H), 2.41-2.29 (m, 2H), 2.26-2.16(m, 2H), 1.94-1.82 (m, 2H), 1.49 (d, 3H, J=7.2 Hz), 1.47 (d, 3H, J=7.2Hz); ¹³C NMR (100 MHz, CD₃OD) δ: 173.6, 173.4, 167.9, 167.1, 139.7,139.7, 129.5, 129.5, 128.4, 128.4, 128.2, 128.2, 91.1, 90.9, 71.7, 70.8,60.7, 59.8, 58.8, 44.2, 44.0, 32.3, 32.2, 32.2, 31.2, 27.2, 26.7, 16.8,16.7. HRMS calcd for C₁₉H₂₇N₄O₄: 375.2027. found 375.2028.

Example 18 Preparation of(3S,8aS)—N-(4-chlorophenyl)-3-((S)-2-(methylamino)propanamido)-4-oxohexahydro-2H-pyrrolo[2,1-b][1,3]oxazine-6-carboxamide

Same procedure as Example 17 with carboxylic acid (105 mg, 0.362 mmol,1.0 equiv), aldehyde (50 mg, 0.380 mmol, 1.05 equiv), isocyanide (50 mg,0.362 mmol, 1.0 equiv) and 7 M ammonia in MeOH (103 μL, 0.723 mmol, 2.0equiv) in TFE (3 mL). The resultant oil was combined with TFA (166 μL,2.17 mmol, 6 equiv) in DCM (5 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and purified by flash chromatographyon basic alumina (3:1 hexanes/EtOAc→DCM→7% MeOH/DCM) to yield theproduct as a 1:1 diastereomixture of the free base (98 mg, 69% over 2steps). ¹H NMR (400 MHz, CDCl₃) δ: 8.53 (bs, 1H), 7.58 (d, 2H, J=3.2Hz), 7.57 (d, 2H, J=3.6 Hz), 7.32 (d, 2H, J=2.0 Hz), 7.30 (d, 2H, J=3.6Hz), 5.29 (dd, 1H, J=5.2, 7.2 Hz), 5.21 (dd, 1H, J=4.8, 6.8 Hz),4.71-4.68 (m, 2H), 4.66-4.63 (m, 1H), 4.49 (d, 1H, J=8.8 Hz), 4.31 (dd,1H, J=6.8, 11.6 Hz), 4.26 (dd, 1H, J=6.4, 11.6 Hz), 4.01 (dd, 1H, J=2.8,11.6 Hz), 3.94 (dd, 1H, J=2.8, 11.6 Hz), 3.62 (q, 1H, J=6.8 Hz), 3.60(q, 1H, J=6.8 Hz), 2.56 (s, 6H), 2.47-2.35 (m, 2H), 2.30-2.25 (m, 2H),2.13-2.07 (m, 2H), 2.02-1.87 (m, 2H), 1.45 (d, 3H, J=7.2 Hz), 1.43 (d,3H, J=7.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 171.8, 171.6, 167.8, 167.3,138.5, 138.2, 130.5, 130.3, 129.8, 129.8, 122.8, 122.5, 91.0, 90.9,71.4, 70.9, 61.1, 60.3, 59.0, 32.6, 32.6, 32.3, 31.3, 27.1, 26.7, 17.2,17.0. HRMS calcd for C₁₈H₂₄ClN₄O₄: 395.1481. found 395.1479.

Example 19 Preparation of(3S,8aS)-3-((S)-2-(methylamino)propanamido)-4-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)hexahydro-2H-pyrrolo[2,1-b][1,3]oxazine-6-carboxamide

Same procedure as Example 17 with carboxylic acid (97 mg, 0.334 mmol,1.0 equiv), aldehyde (46 mg, 0.351 mmol, 1.05 equiv), isocyanide (53 mg,0.334 mmol, 1.0 equiv) and 7 M ammonia in MeOH (97 μL, 0.668 mmol, 2.0equiv) in TFE (3 mL). The resultant oil was combined with TFA (177 μL,1.55 mmol, 6 equiv) in DCM (5 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and purified by flash chromatographyon basic alumina (3:1 hexanes/EtOAc→DCM→7% MeOH/DCM) to yield theproduct as the free base (72 mg, 67% over 2 steps). Some of the materialwas further purified by preparative scale HPLC for use in biologicalassays. ¹H NMR (400 MHz, CDCl₃) δ: 8.51 (s, 1H), 7.40-7.36 (m, 1H),7.17-7.06 (m, 7H), 5.24 (dd, 1H, J=4.8, 6.4 Hz), 5.17 (dd, 1H, J=4.8,8.0 Hz), 5.10-5.04 (m, 2H), 4.66-4.62 (m, 2H), 4.57 (t, J=8.0 Hz), 4.35(d, 1H, J=7.6 Hz), 4.27 (dd, 1H, J=6.4, 11.6 Hz), 4.24 (dd, 1H, J=6.0,12.0 Hz), 3.76-3.65 (m, 2H), 2.87-2.72 (m, 4H), 2.63 (s, 3H), 2.61 (s,3H), 2.43-2.31 (m, 2H), 2.28-2.17 (m, 2H), 2.05-1.88 (m, 7H), 1.86-1.74(m, 5H), 1.52 (d, 3H, J=7.2 Hz), 1.49 (d, 3H, J=7.2 Hz); ¹³C NMR (100MHz, CDCl₃) δ: 206.6, 172.9, 172.8, 171.7, 167.7, 167.0, 138.7, 138.5,137.6, 137.6, 130.1, 129.9, 129.7, 129.3, 128.2, 128.1, 127.2, 127.2,127.1, 91.1, 91.0, 71.6, 70.9, 60.8, 59.8, 58.9, 58.8, 58.8, 32.3, 32.3,32.2, 31.3, 31.3, 31.2, 30.2, 30.2, 27.2, 26.8, 21.8, 21.5, 16.8, 16.7.HRMS calcd for C₂₂H₃₀N₄O₄Na: 437.21593. found 437.20535.

Example 20 Preparation of(2R,3S,8aS)-2-methyl-3-((S)-2-(methylamino)propanamido)-4-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)hexahydro-2H-pyrrolo[2,1-b][1,3]oxazine-6-carboxamide

Same procedure as Example 17 with carboxylic acid (85 mg, 0.279 mmol,1.0 equiv), aldehyde (39 mg, 0.293 mmol, 1.05 equiv), isocyanide (44 mg,0.279 mmol, 1.0 equiv) and 7 M ammonia in MeOH (80 μL, 0.559 mmol, 2.0equiv) in TFE (3 mL). The resultant oil was combined with TFA (128 μL,1.67 mmol, 6 equiv) in DCM (5 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and purified by flash chromatographyon basic alumina (3:1 hexanes/EtOAc→DCM→7% MeOH/DCM) to yield theproduct as a slightly impure free base (94 mg, yield not calculated).Some of the material was further purified by preparative scale HPLC foruse in biological assays. ¹H NMR (400 MHz, DMSO-d6) δ: 8.28 (d, 1H,J=8.8 Hz), 8.26 (d, 1H, J=8.8 Hz), 8.24 (s, 2H), 8.18 (d, 1H, J=8.8 Hz),8.00 (d, 1H, J=8.8 Hz), 7.28 (d, 1H, J=7.2 Hz), 7.16-7.06 (m, 6H), 5.25(t, 1H, J=5.6 Hz), 5.20 (dd, 1H, J=5.2, 7.6 Hz), 4.99-4.92 (m, 2H), 4.60(dd, 1H, J=5.6, 8.4 Hz), 4.50 (dd, 1H, J=5.2, 8.4 Hz), 4.46 (t, 1H,J=7.2 Hz), 4.34-4.27 (m, 2H), 4.24 (t, 2H, J=8.4 Hz), 3.13 (q, 1H, J=6.8Hz), 3.09 (q, 1H, J=6.8 Hz), 2.76-2.70 (m, 3H), 2.24 (s, 3H), 2.22 (s,3H), 1.93-1.80 (m, 6H), 1.80-1.60 (m, 6H), 1.17 (d, 3H, J=6.8 Hz), 1.15(d, 3H, J=6.8 Hz), 1.07 (d, 3H, J=6.4 Hz), 1.00 (d, 3H, J=6.4 Hz); ¹³CNMR (100 MHz, DMSO-d6) δ: 174.1, 170.3, 169.9, 165.7, 165.2, 137.6,137.4, 137.0, 136.9, 128.7, 128.5, 128.3, 127.7, 126.7, 126.6, 125.8,125.7, 99.5, 87.7, 87.6, 73.4, 72.6, 59.2, 58.8, 58.7, 57.9, 50.5, 50.3,46.6, 46.5, 34.0, 33.7, 30.7, 30.0, 29.9, 28.8, 28.8, 26.0, 25.7, 20.5,18.9, 18.7, 16.5. HRMS calcd for C₂₃H₃₂N₄O₄Na: 451.23158. found451.23286.

Example 21 Preparation of(2R,3S,8aS)-2-methyl-3-((S)-2-(methylamino)propanamido)-N-(naphthalen-1-yl)-4-oxohexahydro-2H-pyrrolo[2,1-b][1,3]oxazine-6-carboxamide

Same procedure as Example 17 with carboxylic acid (100 mg, 0.328 mmol,1.0 equiv), aldehyde (46 mg, 0.344 mmol, 1.05 equiv), isocyanide (50 mg,0.328 mmol, 1.0 equiv) and 7 M ammonia in MeOH (94 μL, 0.657 mmol, 2.0equiv) in TFE (3 mL). The resultant oil was combined with TFA (151 μL,1.97 mmol, 6 equiv) in DCM (5 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and purified by flash chromatographyon basic alumina (1:1 hexanes/EtOAc→DCM→7% MeOH/DCM) to yield theproduct as the free base (88 mg, 63% over 2 steps). Some of the materialwas further purified by preparative scale HPLC for use in biologicalassays. ¹H NMR (400 MHz, CD₃OD) δ: 8.53 (bs, 1H), 8.13-8.09 (m, 1H),8.05 (d, 1H, J=6.8 Hz), 7.92-7.87 (m, 2H), 7.81 (t, 2H, J=6.4 Hz),7.56-7.46 (m, 8H), 5.29 (dd, 1H, J=5.2, 8.0 Hz), 5.21 (dd, 1H, J=4.8,8.4 Hz), 4.83 (t, 1H, J=8.4 Hz), 4.71-4.67 (m, 2H), 4.62 (d, 1H, J=4.0Hz), 4.36-4.24 (m, 2H), 3.70 (q, 1H, J=6.8 Hz), 3.65 (q, 1H, J=6.8 Hz),2.59 (s, 3H), 2.52 (s, 3H), 2.42-2.32 (m, 2H), 2.31-2.18 (m, 2H),2.16-2.02 (m, 2H), 1.96-1.85 (m, 1H), 1.50 (d, 3H, J=6.8 Hz), 1.38 (d,3H, J=7.2 Hz), 1.24 (t, 6H, J=6.8 Hz); ¹³C NMR (100 MHz, CD₃OD) δ:173.3, 173.2, 172.7, 172.4, 168.3, 167.5, 135.7, 135.7, 134.0, 133.7,130.6, 130.6, 129.3, 129.2, 128.2, 128.1, 127.5, 127.4, 127.3, 127.2,126.4, 126.4, 124.6, 124.3, 124.1, 123.8, 91.0, 90.9, 76.3, 75.7, 60.6,59.5, 59.1, 58.9, 52.8, 52.5, 32.6, 32.4, 32.2, 31.2, 26.7, 26.2, 17.3,17.2, 16.7. HRMS calcd for C₂₃H₂₉N₄O₄: 425.2183. found 425.2181.

Example 22 Preparation of(2R,3S,8aS)—N-benzhydryl-2-methyl-3-((S)-2-(methylamino)propanamido)-4-oxohexahydro-2H-pyrrolo[2,1-b][1,3]oxazine-6-carboxamide

Same procedure as Example 17 with carboxylic acid (105 mg, 0.345 mmol,1.0 equiv), aldehyde (47 mg, 0.362 mmol, 1.05 equiv), isocyanide (67 mg,0.345 mmol, 1.0 equiv) and 7 M ammonia in MeOH (99 μL, 0.690 mmol, 2.0equiv) in TFE (3 mL). The resultant oil was combined with TFA (159 μL,2.07 mmol, 6 equiv) in DCM (5 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and purified by flash chromatographyon basic alumina (1:1 hexanes/EtOAc→DCM→7% MeOH/DCM) to yield theproduct as the free base (73 mg, 46% over 2 steps). ¹H NMR (400 MHz,CD₃OD) δ: 7.38-7.18 (m, 20H), 6.17 (s, 1H), 6.15 (s, 1H), 5.21 (dd, 1H,J=5.2, 8.0 Hz), 5.13 (dd, 1H, J=4.8, 8.8 Hz), 4.66 (t, 1H, J=7.6 Hz),4.62 (d, 1H, J=4.4 Hz), 4.56 (d, 1H, J=4.4 Hz), 4.47 (d, 1H, J=8.4 Hz),4.28 (dd, 1H, J=4.4, 6.4 Hz), 4.22 (dd, 1H, J=4.4, 6.4 Hz), 3.25 (q, 1H,J=6.8 Hz), 3.21 (q, 1H, J=6.8 Hz), 2.36 (s, 3H), 2.30 (s, 3H), 2.39-2.25(m, 2H), 2.19-2.12 (m, 2H), 2.06-1.86 (m, 4H), 1.85-1.79 (m, 2H), 1.31(d, 3H, J=6.8 Hz), 1.26 (d, 3H, J=7.2 Hz), 1.20 (d, 3H, J=6.4 Hz), 1.18(d, 3H, J=6.4 Hz); ¹³C NMR (100 MHz, CD₃OD) δ: 176.8, 176.6, 173.0,172.7, 168.0, 167.6, 143.0, 142.8, 142.6, 142.6, 129.7, 129.6, 129.5,129.4, 128.9, 128.8, 128.7, 128.6, 128.5, 128.5, 128.3, 128.1, 90.7,90.6, 76.3, 75.5, 60.4, 60.3, 60.0, 59.2, 58.5, 58.4, 52.5, 52.2, 34.2,34.1, 32.1, 31.1, 29.5, 26.7, 26.1, 19.2, 19.1, 16.8, 16.7. HRMS calcdfor C₂₆H₃₂N₄O₄Na: 487.23158. found 487.23308.

Example 23 General synthetic scheme for the preparation of7,5-heterobicyclic Smac peptidomimetics

Example 24 Preparation of(4S,9aS)-4-amino-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

A mixture of Boc-N-HSer-OH (318 mg, 1.45 mmol, 1.0 equiv), aldehyde (201mg, 1.52 mmol, 1.05 equiv), isocyanide (228 mg, 1.45 mmol, 1.0 equiv)and 7 M ammonia in MeOH (414 μL, 2.90 mmol, 2.0 equiv) in TFE (5 mL) wasstirred under microwave irradiation at a set temperature of 80° C. for20 min. The mixture was then transferred to a round bottom flask andconcentrated in vacuo, then 1 M NaOH (15 mL) was added and the mixturewas extracted with DCM (3×7 mL). The organics were dried over Na₂SO₄,filtered and concentrated in vacuo. The resultant oil was combined withTFA (834 μL, 10.9 mmol, 8 equiv) in DCM (5 mL) and stirred at 35° C. for14 h. The mixture was concentrated in vacuo and the crude product usedwithout further purification in the next step.

Example 25 Preparation of tert-butylmethyl((2S)-1-oxo-1-(((4S,9aS)-5-oxo-7-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]oxazepin-4-yl)amino)propan-2-yl)carbamate

To a solution of amine (622 mg, 1.36 mmol, 1.0 equiv), Boc-N-Me-Ala-OH(276 mg, 1.36 mmol, 1.0 equiv), HOBT.xH₂O (229 mg, 1.50 mmol, 1.1 equiv)and NMM (598 μL, 5.44 mmol, 4 equiv) in THF (15 mL) at 0° C. was addedEDC.HCl (274 mg, 1.43 mmol, 1.05 equiv). After 30 min the cold bath wasremoved. The solution stirred for 14 h and then was quenched withsaturated aqueous NaHCO₃ (25 mL), extracted with ethyl acetate (2×20mL), dried over sodium sulfate and then concentrated in vacuo. Theresultant oil was purified by flash chromatography on silica gel(2:1→1:1→1:3 hexanes/EtOAc) to yield, after 3 steps, partially separateddiastereomers S-isomer (30 mg, 4%, ˜3:1 d.r.) and R-isomer (40 mg, 5%,˜3:1 d.r.), along with unseparated R+S isomers (267 mg, 35%). Data forS-isomer: R_(f)=0.40 (1:3 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ:7.23-7.05 (m, 4H), 6.84 (d, 1H, J=8.0 Hz), 5.22 (t, 1H, J=6.4 Hz),5.18-5.08 (m, 1H), 4.69 (dd, 1H, J=5.6, 10.8 Hz), 4.62 (d, 1H, J=7.6Hz), 4.13-4.03 (m, 1H), 3.95 (q, 1H, J=12.8 Hz), 2.75 (s, 3H), 2.80-2.74(m, 1H), 2.47-2.37 (m, 1H), 2.17-1.89 (m, 4H), 1.88-1.69 (m, 5H), 1.43(s, 9H), 1.32 (d, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 171.4,169.9, 169.8, 137.6, 137.3, 136.9, 136.7, 129.3, 129.2, 128.6, 128.3,27.4, 127.3, 126.4, 126.2, 90.3, 90.0, 70.7, 70.6, 61.1, 60.6, 53.1,52.6, 47.7, 47.7, 33.3, 32.7, 32.5, 30.2, 30.1, 29.8, 29.3, 29.3, 28.4,28.4, 25.9, 20.5, 20.1. Data for R-isomer: R_(f)=0.55 (1:3hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 7.24-7.11 (m, 4H), 7.11-7.05(m, 1H), 6.69 (bs, 1H), 5.21 (d, 1H, J=5.6 Hz), 5.10 (q, 1H, J=6.8 Hz),4.75 (dd, 1H, J=7.6, 11.6 Hz), 4.55 (d, 1H, J=8.0 Hz), 4.47 (t, 1H,J=8.8 Hz), 4.01 (d, 1H, J=12.8 Hz), 3.97 (t, 1H, J=12.4 Hz), 2.82-2.75(m, 2H), 2.77 (s, 3H), 2.45-2.33 (m, 1H), 2.32-2.24 (m, 1H), 2.24-2.13(m, 2H), 2.06-1.93 (m, 3H), 1.84-1.76 (m, 2H), 1.74-1.64 (m, 5H), 1.45(s, 9H), 1.34 (d, 3H, J=6.8 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 172.1,171.0, 169.8, 137.6, 136.7, 129.3, 128.6, 127.4, 126.4, 90.0, 70.6,66.0, 61.2, 53.2, 47.8, 33.3, 32.7, 30.2, 29.3, 28.5, 25.8, 20.2, 14.0.HRMS calcd for C₂₈H₄₀N₄O₆: 551.2840. found 551.2838.

Example 26 Preparation of(4S,7S,9aS)-4-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

To a solution of carbamate (30 mg, 0.057 mmol, 1 equiv, ˜7:3 d.r.) inDCM (2 mL) was added TFA (35 μL, 0.454 mmol, 8 equiv). After stirringfor 20 h at 23° C., the solution was concentrated. The product waseluted through a short plug (˜400 mg) of Silicyle® TMA-chloride ionexchange resin with MeOH to yield product.HCl (26 mg, quantitative) asthe major diastereomer (˜7:3). ¹H NMR (400 MHz, CD₃OD) δ: 7.38-7.35 (m,1H), 7.15-7.06 (m, 3H), 5.41-5.38 (m, 1H), 5.09-5.03 (m, 1H), 4.42 (t,1H, J=6.4 Hz), 4.15 (dt, 1H, J=2.8, 12.8 Hz), 4.04-3.96 (m, 1H),3.95-3.89 (m, 1H), 2.86-2.71 (m, 2H), 2.67 (s, 3H), 2.32-2.25 (m, 1H),2.12 (q, 2H, J=7.2 Hz), 2.06-1.96 (m, 2H), 1.94-1.85 (m, 1H), 1.85-1.74(m, 2H), 1.58 (d, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CD₃OD) δ: 173.4,172.7, 172.7, 172.2, 169.6, 169.3, 138.6, 138.5, 137.8, 137.7, 130.0,130.0, 129.6, 129.2, 128.2, 128.1, 127.1, 91.0, 71.3, 71.2, 62.4, 62.4,58.4, 58.3, 54.4, 54.2, 34.0, 33.6, 33.3, 33.2, 31.8, 31.3, 31.2, 30.2,30.2, 28.2, 28.0, 21.7, 21.6, 16.4, 16.4. HRMS calcd for C₂₃H₃₃N₄O₄:429.2496. found 429.2495.

Example 27 Preparation of(4S,9aS)-4-amino-N-(naphthalen-1-yl)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

Same procedure as Example 24 with Boc-N-HSer-OH (150 mg, 0.684 mmol, 1.0equiv), aldehyde (95 mg, 0.718 mmol, 1.05 equiv), isocyanide (105 mg,0.684 mmol, 1.0 equiv) and 7 M ammonia in MeOH (195 μL, 1.37 mmol, 2.0equiv) in TFE (4 mL). The resultant oil was combined with TFA (314 μL,4.10 mmol, 6 equiv) in DCM (5 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and the crude product used withoutfurther purification in the next step.

Example 28 Preparation of tert-butylmethyl((2S)-1-(((4S,9aS)-7-(naphthalen-1-ylcarbamoyl)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepin-4-yl)amino)-1-oxopropan-2-yl)carbamate

Same procedure as Example 25 above using amine derivative (209 mg, 0.615mmol, 1.0 equiv), Boc-N-Me-Ala-OH (125 mg, 0.615 mmol, 1.0 equiv),HOBT.xH₂O (104 mg, 0.677 mmol, 1.1 equiv), NMM (338 μL, 3.08 mmol, 5equiv [to soak up xs TFA]) and EDC.HCl (124 mg, 0.646 mmol, 1.05 equiv)in THF (10 mL). The resultant oil was purified by flash chromatographyon silica gel (2:1→1:1→1:3 hexanes/EtOAc) to yield, after 3 steps,S-isomer (43 mg, 12%, ˜6:1 d.r.) and R-isomer (37 mg, 10%, ˜6:1 d.r.),along with unseparated mixture (49 mg, 14%). Data for S-isomer:R_(f)=0.33 (1:3 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) ␣: 9.11 (s, 1H),8.10 (d, 1H, J=7.6 Hz), 7.98 (d, 1H, J=8.8 Hz), 7.86 (d, 1H, J=8.0 Hz),7.67 (d, 1H, J=8.4 Hz), 7.56-7.44 (m, 3H), 7.32 (s, 1H), 5.33 (t, 1H,J=6.4 Hz), 4.90 (d, 1H, J=6.4 Hz), 4.81 (dd, 1H, J=5.2, 10.4 Hz), 4.19(dt, 1H, J=2.8, 12.8 Hz), 4.07-3.98 (m, 1H), 2.78 (s, 3H), 2.59-2.46 (m,2H), 2.32-2.21 (m, 1H), 2.01-1.91 (m, 3H), 1.85-1.74 (m, 1H), 1.44 (s,9H), 1.36 (d, 3H, J=6.8 Hz); ¹³C NMR (100 MHz, CDCl₃) ␣: 172.1, 171.4,169.1, 168.5, 134.1, 132.7, 128.9, 126.6, 126.5, 126.0, 125.9, 125.5,120.7, 119.8, 90.7, 70.8, 61.2, 52.8, 32.8, 32.6, 30.2, 28.5, 28.4,25.6. Data for R-isomer: R_(f)=0.42 (1:3 hexanes/EtOAc). ¹H NMR (400MHz, CDCl₃) δ: 9.47 (s, 1H), 8.03 (d, 1H, J=7.2 Hz), 7.94 (d, 1H, J=7.6Hz), 7.82 (d, 1H, J=7.6 Hz), 7.63 (d, 1H, J=8.0 Hz), 7.55 (s, 1H),7.50-7.40 (m, 2H), 7.31 (s, 1H), 5.21 (s, 1H), 4.96 (d, 1H, J=7.6 Hz),4.85-4.78 (m, 1H), 4.43 (t, 1H, J=8.8 Hz), 4.14 (d, 1H, J=12.8 Hz), 3.99(t, 1H, J=12.0 Hz), 2.79 (s, 3H), 2.61-2.53 (m, 1H), 2.26-2.14 (m, 1H),2.11-1.97 (m, 2H), 1.90-1.78 (m, 1H), 1.46 (s, 9H), 1.34 (d, 3H, J=7.2Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 175.0, 173.3, 172.4, 168.5, 134.1,132.8, 128.7, 126.5, 126.1, 125.8, 125.4, 121.0, 119.5, 90.3, 70.6,65.9, 61.6, 53.2, 49.2, 33.6, 32.5, 30.3, 30.3, 28.5, 28.5, 28.4, 24.6.HRMS calcd for C₂₈H₃₆N₄O₆Na: 547.25271. found 547.25362.

Example 29 Preparation of(4S,7S,9aS)-4-((S)-2-(methylamino)propanamido)-N-(naphthalen-1-yl)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

To a solution of carbamate (12 mg, 0.023 mmol, 1 equiv, ˜6:1 d.r.) inDCM (1 mL) was added TFA (14 μL, 0.183 mmol, 8 equiv). After stirringfor 20 h at 23° C., the solution was concentrated to yield product.TFA(12 mg, quantitative) as the major diastereomer. ¹H NMR (400 MHz, CD₃OD)δ: 8.12-8.08 (m, 1H), 7.92-7.88 (m, 1H), 7.79 (d, 1H, J=8.4 Hz), 7.67(dd, 1H, J=1.2, 7.2 Hz), 7.56-7.45 (m, 3H), 5.48 (q, 1H, J=2.8 Hz), 4.99(d, 1H, J=12.0 Hz), 4.75 (t, 2H, J=6.8 Hz), 4.21 (dt, 1H, J=2.8, 12.4Hz), 4.10-4.00 (m, 1H), 3.96-3.87 (m, 1H), 2.68 (s, 3H), 2.44-2.29 (m,2H), 2.22-2.07 (m, 2H), 1.83 (dd, 1H, J=2.0, 14.4 Hz), 1.60 (d, 3H,J=6.8 Hz); ¹³C NMR (100 MHz, CD₃OD) δ: 172.9, 172.5, 169.7, 135.7,134.0, 129.9, 127.3, 127.2, 126.5, 123.5, 91.1, 71.4, 62.8, 58.4, 54.3,49.0, 33.8, 33.4, 31.8, 28.1, 16.4. HRMS calcd for C₂₃H₂₈N₄O₄Na:447.20028. found 447.20189.

Example 30 Preparation of(4S,9aS)-4-amino-7-(1H-indole-1-carbonyl)hexahydropyrrolo[2,1-b][1,3]oxazepin-5(2H)-one

Same procedure as Example 24 with Boc-N-HSer-OH (313 mg, 1.43 mmol, 1.0equiv), aldehyde (198 mg, 1.50 mmol, 1.05 equiv), isocyanide (273 mg,1.43 mmol, 1.0 equiv) and 7 M ammonia in MeOH (408 μL, 2.85 mmol, 2.0equiv) in TFE (5 mL). The resultant oil was combined with TFA (1.09 mL,14.3 mmol, 10 equiv) in DCM (5 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and the crude product used withoutfurther purification in the next step.

Example 31 Preparation of tert-Butyl((2S)-1-(((4S,9aS)-7-(1H-indole-1-carbonyl)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepin-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Same procedure as Example 25 above using crude amine (611 mg, 1.43 mmol,1.0 equiv), Boc-N-Me-Ala-OH (291 mg, 1.43 mmol, 1.0 equiv), HOBT.xH₂O(241 mg, 1.57 mmol, 1.1 equiv), NMM (786 μL, 7.15 mmol, 5 equiv [to soakup xs TFA]) and EDC.HCl (288 mg, 1.50 mmol, 1.05 equiv) in THF (15 mL).The resultant oil was purified by flash chromatography on silica gel(2:1→1:1→1:4 hexanes/EtOAc) to yield, after 3 steps, S-isomer (150 mg,21%) and R-isomer (144 mg, 20%). Data for S-isomer: R_(f)=0.27 (1:3hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 8.51 (d, 1H, J=8.4 Hz), 7.57(d, 1H, J=8.0 Hz), 7.50 (d, 1H, J=4.0 Hz), 7.35 (t, 1H, J=8.4 Hz), 7.28(t, 1H, J=7.6 Hz), 7.16 (s, 1H), 6.69 (d, 1H, J=3.6 Hz), 5.35 (dd, 1H,J=3.6, 6.4 Hz), 5.28 (dd, 1H, J=4.8, 8.0 Hz), 4.80 (dd, 1H, J=6.0, 10.8Hz), 4.75-4.65 (m, 1H), 4.31 (dt, 1H, J=3.2, 12.8 Hz), 4.12 (q, 1H,J=7.2 Hz), 4.05 (t, 1H, J=13.2 Hz), 2.76 (s, 3H), 2.44-2.31 (m, 2H),2.30-2.19 (m, 2H), 2.05-1.98 (m, 2H), 1.42 (s, 9H), 1.34 (d, 3H, J=7.2Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 171.1, 170.8, 168.8, 135.9, 130.2,125.3, 124.0, 124.0, 120.8, 117.0, 110.0, 89.7, 80.6, 80.6, 77.2, 70.8,64.3, 60.4, 59.7, 53.0, 32.6, 30.3, 28.3, 28.3, 28.3, 27.2, 21.0. Datafor R-isomer: R_(f)=0.50 (1:3 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ:8.38 (s, 1H), 7.57 (d, 1H, J=7.6 Hz), 7.49 (d, 1H, J=4.0 Hz), 7.35 (t,1H, J=7.2 Hz), 7.28 (d, 1H, J=7.6 Hz), 7.18 (s, 1H), 6.71 (d, 1H, J=3.6Hz), 5.44-5.39 (m, 2H), 4.88 (dd, 1H, J=5.6, 11.2 Hz), 4.75-4.69 (m,1H), 4.47 (t, 2H, J=8.8 Hz), 4.31-4.24 (m, 1H), 4.17 (dt, 1H, J=3.2,12.8 Hz), 4.13-4.04 (m, 1H), 3.72-3.66 (m, 1H), 3.56-3.48 (m, 1H), 2.79(s, 3H), 2.66-2.54 (m, 1H), 2.37 (sept, 1H, J=6.8 Hz), 2.21-2.06 (m,4H), 1.81 (qd, 1H, J=3.6, 14.0 Hz), 1.67-1.58 (m, 1H), 1.43 (s, 9H),1.33 (d, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 172.3, 171.1, 168.7,135.8, 130.2, 125.4, 124.1, 123.8, 121.0, 116.7, 110.3, 89.6, 70.7,65.8, 60.0, 53.0, 49.1, 33.1, 32.2, 30.4, 28.4, 28.4, 28.4, 26.9. HRMScalcd for C₂₆H₃₄N₄O₆Na: 521.2371. found 521.2372.

Example 32 Preparation of(S)—N-((4S,7S,9aS)-7-(1H-indole-1-carbonyl)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepin-4-yl)-2-(methylamino)propanamide

Same procedure as Example 29 above using carbamate (52 mg, 0.104 mmol, 1equiv) and TFA (64 μL, 0.834 mmol, 8 equiv) in DCM (2 mL). Afterstirring for 20 h at 23° C., the solution was concentrated to yieldproduct.TFA (53 mg, quantitative) as a single diastereomer. ¹H NMR (400MHz, CD₃OD) δ: 8.39 (d, 1H, J=8.0 Hz), 7.84 (d, 1H, J=4.0 Hz), 7.58 (d,1H, J=7.2 Hz), 7.33-7.24 (m, 2H), 6.73 (d, 1H, J=4.0 Hz), 5.50-5.46 (m,1H), 5.34 (t, 1H, J=6.8 Hz), 4.26 (dt, 1H, J=3.2, 12.4 Hz), 4.10-4.02(m, 1H), 3.92-3.84 (m, 2H), 2.65 (s, 3H), 2.28 (qd, 1H, J=3.6, 12.4 Hz),2.19-2.05 (m, 2H), 1.86 (d, 1H, J=14.0 Hz), 1.55 (dd, 2H, J=4.0, 7.2Hz), 1.50 (d, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CD₃OD) δ: 172.2, 171.0,169.6, 137.2, 131.9, 126.0, 126.0, 125.0, 122.0, 117.4, 110.7, 90.9,71.4, 61.5, 58.3, 54.4, 49.0, 33.7, 33.2, 31.7, 28.3, 16.3. HRMS calcdfor C₂₁H₂₆N₄O₄Na: 421.18463. found 421.18593.

Example 33 Preparation of(S)—N-((4S,7R,9aS)-7-(1H-Indole-1-carbonyl)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepin-4-yl)-2-(methylamino)propanamide

Same procedure as Example 29 above using carbamate (51 mg, 0.102 mmol, 1equiv) and TFA (117 μL, 1.02 mmol, 10 equiv) in DCM (2 mL). Afterstirring for 20 h at 23° C., the solution was concentrated to yieldproduct.TFA (52 mg, quantitative) as a single diastereomer. ¹H NMR (400MHz, CDCl₃) δ: 8.34 (d, 1H, J=8.0 Hz), 7.85 (d, 1H, J=4.0 Hz), 7.59 (d,1H, J=6.8 Hz), 7.34-7.24 (m, 2H), 6.75 (d, 1H, J=4.0 Hz), 5.57-5.53 (m,2H), 5.09 (dd, 1H, J=2.0, 11.2 Hz), 4.67 (dd, 1H, J=9.2, 10.8 Hz), 4.46(td, 1H, J=1.6, 8.8 Hz), 4.35-4.27 (m, 1H), 4.19 (dt, 1H, J=2.8, 12.4Hz), 4.12-4.04 (m, 1H), 3.90 (t, 2H, J=6.8 Hz), 3.74-3.66 (m, 1H), 2.68(s, 3H), 2.62-2.53 (m, 2H), 2.39-2.27 (m, 2H), 2.07 (dd, 2H, J=7.2, 13.2Hz), 1.93-1.87 (m, 1H), 1.55 (d, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CD₃OD)δ: 176.8, 172.5, 171.1, 170.4, 169.4, 137.1, 131.9, 126.1, 125.9, 125.1,122.0, 117.4, 111.0, 90.9, 71.3, 67.2, 61.5, 58.4, 58.2, 54.3, 50.2,34.1, 33.2, 31.8, 31.8, 29.2, 27.9, 16.3, 16.2. HRMS calcd forC₂₁H₂₇N₄O₄: 399.2027. found 399.2028.

Example 34 Preparation of(4S,7S,9aS)-4-amino-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide

Same procedure as Example 24 with Boc-N-HCys(Trt)-OH (665 mg, 1.39 mmol,1.0 equiv), aldehyde (193 mg, 1.46 mmol, 1.05 equiv), isocyanide (219mg, 1.39 mmol, 1.0 equiv) and 7 M ammonia in MeOH (398 μL, 2.78 mmol,2.0 equiv) in TFE (5 mL). The resultant oil was combined with TFA (1.07mL, 13.9 mmol, 10 equiv) in DCM (5 mL) and stirred at 60° C. for 6 h.The mixture was concentrated in vacuo, then partially purified (tritylbyproduct removed and more polar product(s) collected) by flashchromatography on basic alumina (3:1 hexanes/EtOAc→DCM→7% MeOH/DCM) toyield semi-pure product.

Example 35 Preparation of tert-Butylmethyl((2S)-1-oxo-1-(((4S,9aS)-5-oxo-7-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl)amino)propan-2-yl)carbamate

Same procedure as Example 25 above using crude amine (658 mg, 1.39 mmol,1.0 equiv), Boc-N-Me-Ala-OH (282 mg, 1.39 mmol, 1.0 equiv), HOBT.xH₂O(234 mg, 1.39 mmol, 1.1 equiv), NMM (917 μL, 8.34 mmol, 6 equiv [to soakup xs TFA]) and EDC.HCl (280 mg, 1.46 mmol, 1.05 equiv) in THF (18 mL).The resultant oil was purified by flash chromatography on silica gel(1:1→1:2→1:3 hexanes/EtOAc) to yield, after 3 steps, S-isomer (121 mg,16%, ˜3:1 d.r.) and R-isomer (100 mg, 13%, ˜3:1 d.r.) along withunseparated mixture (136 mg, 18%). Data for S-isomer: R_(f)=0.27 (1:3hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 7.32 (d, 1H, J=7.6 Hz),7.25-7.21 (m, 1H), 7.16-7.04 (m, 4H), 5.17 (q, 1H, J=7.2 Hz), 5.08 (t,1H, J=7.2 Hz), 4.74 (d, 1H, J=8.0 Hz), 4.53 (dd, 1H, J=6.0, 10.8 Hz),3.35-3.22 (m, 1H), 2.76 (s, 3H), 2.63-2.46 (m, 1H), 2.20 (d, 1H, J=12.8Hz), 2.12-1.98 (m, 2H), 1.92-1.71 (m, 5H), 1.59 (q, 1H, J=12.4 Hz), 1.43(s, 9H), 1.31 (d, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 171.3,169.6, 169.3, 137.3, 129.2, 129.1, 128.8, 127.2, 126.1, 62.3, 61.8,52.8, 47.6, 33.0, 32.1, 30.4, 30.2, 29.3, 28.4, 28.4, 26.5, 20.5. Datafor R-isomer: R_(f)=0.44 (1:3 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ:7.22-7.12 (m, 4H), 7.09-7.04 (m, 1H), 6.62 (bs, 1H), 5.28 (d, 1H, J=7.6Hz), 5.09 (d, 1H, J=6.4 Hz), 4.66-4.56 (m, 2H), 3.32 (t, 1H, J=12.0 Hz),2.87-2.68 (m, 3H), 2.75 (s, 3H), 2.35-2.19 (m, 3H), 2.08-1.96 (m, 2H),1.85-1.69 (m, 5H), 1.45 (s, 9H), 1.29 (d, 3H, J=7.2 Hz); ¹³C NMR (100MHz, CDCl₃) δ: 170.9, 169.6, 137.6, 136.6, 129.3, 128.6, 127.4, 126.3,63.8, 61.3, 53.5, 47.7, 33.7, 31.7, 30.1, 29.3, 28.5, 28.4, 20.1. HRMScalcd for C₂₈H₄₀N₄O₅SNa: 567.26116. found 567.26151.

Example 36 Preparation of(4S,7S,9aS)-4-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide

Same procedure as Example 24 using carbamate (90 mg, 0.165 mmol, 1equiv, ˜3:1 d.r.) and TFA (126 μL, 1.65 mmol, 10 equiv) in DCM (4 mL).After stirring for 20 h at 32° C., the solution was concentrated. Theproduct was eluted through a short plug (˜500 mg) of Silicyle®TMA-chloride ion exchange resin with MeOH to yield product.HCl (79 mg,quantitative) as the major diastereomer. ¹H NMR (400 MHz, CD₃OD) δ:7.39-7.34 (m, 1H), 7.17-7.05 (m, 4H), 5.46-5.39 (m, 1H), 5.07 (t, 1H,J=6.8 Hz), 4.77 (dd, 1H, J=2.0, 11.2 Hz), 4.57 (dd, 1H, J=5.2, 7.6 Hz),3.94-3.87 (m, 1H), 3.29-3.21 (m, 1H), 3.02 (ddd, 1H, J=2.8, 6.0, 14.4Hz), 2.82-2.75 (m, 2H), 2.66 (s, 3H), 2.60-2.49 (m, 1H), 2.25-2.17 (m,2H), 2.15-2.09 (m, 1H), 2.05-1.95 (m, 2H), 1.95-1.74 (m, 4H), 1.53 (d,3H, J=7.2 Hz); ¹³C NMR (100 MHz, CD₃OD) δ: 172.3, 171.9, 169.5, 138.7,138.5, 137.6, 137.3, 130.2, 130.0, 129.9, 129.5, 128.4, 128.3, 127.2,127.1, 63.9, 63.4, 63.1, 58.4, 58.3, 55.1, 54.2, 54.1, 34.1, 33.3, 31.8,31.8, 31.3, 31.0, 30.1, 30.1, 28.8, 28.5, 21.5, 21.1, 16.4, 16.3. HRMScalcd for C₂₃H₃₃N₄O₃S: 445.2268. found 445.2267.

Example 37 Preparation of(4S,7R,9aS)-4-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide

Same procedure as Example 24 using carbamate (24 mg, 0.0441 mmol, 1equiv, ˜3:1 d.r.) and TFA (34 μL, 0.441 mmol, 10 equiv) in DCM (2 mL).After stirring for 20 h at 32° C., the solution was concentrated. Theproduct was eluted through a short plug (˜500 mg) of Silicyle®TMA-chloride ion exchange resin with MeOH to yield product.HCl (21 mg,quantitative) as the major diastereomer. ¹H NMR (400 MHz, CD₃OD) δ:7.16-7.08 (m, 4H), 5.51 (d, 1H, J=7.2 Hz), 5.08-5.03 (m, 1H), 4.83 (s,1H), 4.57 (d, 1H, J=8.8 Hz), 3.93 (q, 1H, J=7.2 Hz), 3.37-3.34 (m, 1H),2.90 (ddd, 1H, J=2.8, 5.6, 12.0 Hz), 2.82-2.75 (m, 2H), 2.66 (s, 3H),2.60-2.50 (m, 1H), 2.49-2.39 (m, 2H), 2.26-2.19 (m, 1H), 2.10-1.89 (m,6H), 1.86-1.74 (m, 4H), 1.46 (d, 3H, J=6.8 Hz); ¹³C NMR (100 MHz, CD₃OD)δ: 173.3, 172.3, 169.0, 138.7, 137.8, 130.0, 129.8, 129.2, 128.7, 128.1,127.1, 64.6, 62.4, 58.3, 54.6, 53.8, 34.2, 33.7, 32.1, 31.8, 31.2, 30.3,29.6, 21.7, 16.4. HRMS calcd for C₂₃H₃₃N₄O₃S: 445.2268. found 445.2267.

Example 38 Preparation of(4S,11bS)-4-amino-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,4,5,7,11b-hexahydro-[1,3]oxazepino[2,3-a]isoindole-7-carboxamide

Same procedure as Example 24 with Boc-N-HSer-OH (175 mg, 0.800 mmol, 1.0equiv), aldehyde (144 mg, 0.800 mmol, 1.0 equiv), isocyanide (126 mg,0.800 mmol, 1.0 equiv) and 7 M ammonia in MeOH (229 μL, 1.60 mmol, 2.0equiv) in TFE (4 mL). The resultant oil was combined with TFA (490 μL,6.40 mmol, 8 equiv) in DCM (3 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and the crude product used withoutfurther purification in the next step.

Example 39 Preparation of tert-Butylmethyl((2S)-1-oxo-1-(((4S,11bS)-5-oxo-7-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2,3,4,5,7,11b-hexahydro-[1,3]oxazepino[2,3-a]isoindol-4-yl)amino)propan-2-yl)carbamate

Same procedure as Example 25 using crude amine (323 mg, 0.640 mmol, 1.0equiv), Boc-N-Me-Ala-OH (130 mg, 0.640 mmol, 1.0 equiv), HOBT.xH₂O (108mg, 0.704 mmol, 1.1 equiv), NMM (281 μL, 2.56 mmol, 4 equiv) and EDC.HCl(129 mg, 0.672 mmol, 1.05 equiv) in THF (12 mL). The resultant oil waspurified by flash chromatography on silica gel (3:1→1:1→1:2hexanes/EtOAc) to yield, after 3 steps, the unseparated diastereomixture(200 mg, 43%). By NMR, one of the diastereomers seems to exist as a pairof rotational isomers. R_(f)=0.18 (1:1 hexanes/EtOAc). ¹H NMR (400 MHz,CDCl₃) δ: 7.56 (d, 1H, J=7.6 Hz), 7.47 (q, 1H, J=4.4 Hz), 7.44-7.39 (m,5H), 7.38-7.34 (m, 1H), 7.32-7.27 (m, 1H), 7.18-7.14 (m, 3H), 7.10-7.06(m, 1H), 7.03 (d, 1H, J=7.2 Hz), 6.90 (d, 1H, J=7.2 Hz), 6.74 (d, 1H,J=7.6 Hz), 6.44-6.36 (m, 3H), 6.21 (s, 1H), 5.50 (bs, 2H), 5.17-5.10 (m,1H), 5.03 (dd, 1H, J=8.0, 14.4 Hz), 4.88-4.80 (m, 2H), 4.72-4.66 (m,1H), 4.44 (td, 2H, J=8.8 Hz), 4.31-4.15 (m, 5H), 2.80 (s, 3H), 2.79 (s,3H), 2.77 (s, 3H), 2.71 (t, 4H, J=6.4 Hz), 2.22-2.08 (m, 3H), 2.06-1.98(m, 2H), 1.86-1.73 (m, 5H), 1.71- 1.61 (m, 2H), 1.48 (s, 9H), 1.46 (s,9H), 1.35 (d, 3H, J=7.2 Hz), 1.34 (d, 3H, J=7.2 Hz), 1.33 (d, 3H, J=7.2Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 175.0, 172.4, 170.5, 168.3, 168.1,137.7, 137.2, 136.8, 136.5, 136.5, 135.9, 135.7, 135.7, 135.2, 130.7,130.5, 129.4, 129.3, 129.0, 128.7, 127.8, 127.4, 127.2, 126.4, 126.2,125.0, 125.0, 122.9, 122.3, 122.3, 92.0, 91.5, 71.4, 71.4, 66.7, 66.5,65.9, 53.3, 52.8, 49.2, 47.9, 47.7, 30.3, 29.3, 29.2, 28.5, 28.4, 28.4,20.4, 20.2. HRMS calcd for C₃₂H₄₁N₄O₆Na: 599.28401. found 599.28561.

Example 40 Preparation of(4S,11bS)-4-((S)-2-(Methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,4,5,7,11b-hexahydro-[1,3]oxazepino[2,3-a]isoindole-7-carboxamide

Same procedure as Example 29 using carbamate (38 mg, 0.066 mmol, 1equiv) and TFA (40 μL, 0.527 mmol, 8 equiv) in DCM (2 mL). Afterstirring for 20 h at 28° C., the solution was concentrated to yieldproduct.TFA (38 mg, quantitative) as a 1:1 diastereomixture. Data forthe 1:1 diastereomixture: ¹H NMR (400 MHz, CD₃OD) δ: 7.53-7.45 (m, 7H),7.39-7.35 (m, 1H), 7.26 (d, 1H, J=7.2 Hz), 7.16-7.07 (d, 2H, J=2.0 Hz),6.53 (d, 1H, J=1.6 Hz), 6.47 (s, 1H), 5.57 (d, 1H, J=1.6 Hz), 5.47 (s,1H), 5.11-5.03 (m, 3H), 4.66 (dd, 1H, J=9.2, 11.2 Hz), 4.46 (td, 1H,J=2.0, 9.2 Hz), 4.35-4.27 (m, 4H), 3.97 (q, 1H, J=6.8 Hz), 3.88 (q, 1H,J=7.2 Hz), 2.89-2.74 (m, 3H), 2.70 (s, 3H), 2.69 (s, 3H), 2.62-2.54 (m,1H), 2.33 (tt, 1H, J=1.6, 10.8 Hz), 2.02-1.92 (m, 6H), 1.85-1.76 (m,3H), 1.62 (d, 3H, J=7.2 Hz), 1.55 (d, 3H, J=7.2 Hz), 1.54 (d, 3H, J=7.2Hz); ¹³C NMR (100 MHz, CD₃OD) δ:176.8, 172.2, 172.0, 171.0, 170.5,170.4, 169.7, 169.2, 162.8, 162.4, 138.7, 138.6, 138.5, 138.4, 137.7,137.5, 136.9, 136.6, 131.3, 131.3, 130.3, 130.2, 130.1, 130.0, 129.7,129.5, 128.2, 128.2, 127.1, 126.3, 123.2, 123.2, 101.3, 93.2, 92.4,72.1, 72.0, 67.3, 67.2, 66.9, 58.4, 58.4, 58.2, 54.6, 54.4, 50.2, 34.2,33.5, 31.8, 31.8, 31.4, 31.0, 30.2, 30.2, 29.2, 21.6, 21.4, 16.4, 16.4,16.2. HRMS calcd for C₂₇H₃₃N₄O₄: 477.2496. found 477.2493.

Example 41 Preparation of(4S,9aS)-4-Amino-8,8-dimethyl-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

Same procedure as Example 24 with Boc-N-HSer-OH (157 mg, 0.718 mmol, 1.0equiv), aldehyde (144 mg, 0.718 mmol, 1.0 equiv), isocyanide (113 mg,0.718 mmol, 1.0 equiv) and 7 M ammonia in MeOH (205 μL, 1.44 mmol, 2.0equiv) in TFE (4 mL). The resultant oil was combined with TFA (473 μL,7.18 mmol, 10 equiv) in DCM (4 mL) and stirred at 30° C. for 14 h. Themixture was concentrated in vacuo and the crude product used withoutfurther purification in the next step.

Example 42 tert-Butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]oxazepin-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Same procedure as Example 25 using crude amine (270 mg, 0.555 mmol, 1.0equiv), Boc-N-Me-Ala-OH (113 mg, 0.555 mmol, 1.0 equiv), HOBT.xH₂O (93mg, 0.610 mmol, 1.1 equiv), NMM (366 μL, 3.33 mmol, 6 equiv [to soak upxs TFA]) and EDC.HCl (112 mg, 0.582 mmol, 1.05 equiv) in THF (10 mL).The resultant oil was purified by flash chromatography on silica gel(3:1→1:1→1:3 hexanes/EtOAc) to yield, after 3 steps, S-isomer (29 mg,7%, >10:1 d.r.) along with unseparated mixture (168 mg, 42%). Data forS-isomer: R_(f)=0.30 (1:1 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ:7.29-7.25 (m, 2H), 7.17-7.12 (m, 2H), 7.09-7.05 (m, 1H), 6.72 (d, 1H,J=8.0 Hz), 5.24 (t, 1H, J=5.6 Hz), 5.16 (dd, 1H, J=5.6, 6.8 Hz), 4.70(dd, 1H, J=5.6, 11.2 Hz), 4.16 (s, 1H), 4.05-3.98 (m, 1H), 3.93 (q, 1H,J=12.4 Hz), 2.79 (s, 3H), 2.78-2.73 (m, 2H), 2.19 (dd, 1H, J=6.8, 14.0Hz), 2.06-1.96 (m, 2H), 1.88 (dd, 1H, J=6.0, 14.0 Hz), 1.87-1.69 (m,5H), 1.66-1.60 (m, 1H), 1.47 (s, 9H), 1.34 (d, 3H, J=7.2 Hz), 1.18 (s,3H), 1.07 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 170.7, 168.8, 137.3,136.7, 136.6, 129.2, 128.9, 127.4, 126.4, 89.3, 89.2, 70.9, 70.7, 52.6,47.5, 46.1, 39.6, 30.2, 29.7, 29.2, 28.5, 28.4, 23.8, 21.2, 19.9, 14.3,14.0. Data for R-isomer: R_(f)=0.39 (1:3 hexanes/EtOAc). HRMS calcd forC₃₀H₄₄N₄O₆Na: 579.3153. found 579.3155.

Example 43 Preparation of(4S,7S,9aS)-8,8-Dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

Same procedure as Example 29 using carbamate (25 mg, 0.045 mmol, 1equiv, 8:3 d.r.) and TFA (35 μL, 0.449 mmol, 10 equiv) in DCM (1 mL).After stirring for 20 h at 33° C., the solution was concentrated toyield product.TFA (25 mg, quantitative) as the major diastereomer. ¹HNMR (400 MHz, CD₃OD) δ: 8.15 (d, 1H, J=8.4 Hz), 7.32 (d, 1H, J=6.4 Hz),7.17-7.07 (m, 3H), 5.44 (t, 1H, J=6.4 Hz), 5.10 (q, 1H, J=6.8 Hz), 4.14(dt, 1H, J=3.2, 12.0 Hz), 4.08 (s, 1H), 3.99-3.91 (m, 2H), 2.80 (p, 2H,J=6.0 Hz), 2.68 (s, 3H), 2.20 (dd, 1H, J=6.4, 13.2 Hz), 2.08-1.96 (m,3H), 1.89-1.77 (m, 4H), 1.58 (d, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CD₃OD)δ: 172.2, 171.5, 169.6, 138.5, 137.6, 130.1, 129.7, 128.3, 127.1, 117.5,114.6, 90.5, 71.7, 71.3, 58.4, 54.2, 47.0, 40.1, 33.2, 31.8, 31.4, 30.1,29.3, 24.2, 21.4, 16.3. HRMS calcd for C₂₅H₃N₄O₄: 457.2809. found457.2811.

Example 44 Preparation of(4S,7S,9aS)-4-Amino-8,8-dimethyl-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide

Same procedure as Example 24 with Boc-N-HCys(Trt)-OH (500 mg, 1.05 mmol,1.0 equiv), aldehyde (176 mg, 1.10 mmol, 1.05 equiv), isocyanide (165mg, 1.05 mmol, 1.0 equiv) and 7 M ammonia in MeOH (299 μL, 2.09 mmol,2.0 equiv) in TFE (5 mL). The resultant oil was combined with TFA (804μL, 10.5 mmol, 10 equiv) in DCM (5 mL) and stirred at 38° C. for 14 h.The mixture was concentrated in vacuo, then partially purified (tritylbyproduct removed and more polar product(s) collected) by flashchromatography on basic alumina (3:1 hexanes/EtOAc→DCM→7% MeOH/DCM) toyield semi-pure product.

Example 45 Preparation of tert-butyl((2S)-1-(((4S,9aS)-8,8-dimethyl-5-oxo-7-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Same procedure as Example 25 using amine (387 mg, 0.998 mmol, 1.0equiv), Boc-N-Me-Ala-OH (202 mg, 0.998 mmol, 1.0 equiv), HOBT.xH₂O (168mg, 1.10 mmol, 1.1 equiv), NMM (329 μL, 2.99 mmol, 3 equiv) and EDC.HCl(201 mg, 1.05 mmol, 1.05 equiv) in THF (10 mL). The resultant oil waspurified by flash chromatography on silica gel (3:1-+1:1→1:3hexanes/EtOAc) to yield, after 3 steps, S-isomer (12 mg, 2%) andR-isomer (47 mg, 8%), along with unseparated mixture (300 mg, 50%) andunreacted Boc-protected starting material (59 mg, 12%) left over fromthe previous reaction. Data for diastereomixture: ¹H NMR (400 MHz,CD₃OD) δ: 7.32-7.28 (m, 1H), 7.18-7.11 (m, 6H), 7.10-7.06 (m, 2H), 5.49(d, 1H, J=9.2 Hz), 5.41 (q, 1H, J=8.0 Hz), 5.09 (t, 1H, J=6.0 Hz), 5.03(t, 1H, J=6.0 Hz), 5.03 (t, 1H, J=12.0 Hz), 4.69-4.57 (m, 4H), 4.24 (d,1H, J=12.4 Hz), 4.19-4.16 (m, 1H), 3.31 (d, 2H, J=2.0 Hz), 3.29-3.21 (m,2H), 2.86 (s, 6H), 2.81 (s, 3H), 2.80-2.75 (m, 2H), 2.68-2.56 (m, 1H),2.31-2.20 (m, 3H), 2.02-1.75 (m, 13H), 1.48 (s, 18H), 1.37 (d, 3H, J=7.6Hz), 1.32 (d, 3H, J=7.2 Hz), 1.15 (s, 3H), 1.13 (s, 3H); ¹³C NMR (100MHz, CD₃OD) δ: 172.7, 171.8, 171.4, 138.8, 138.5, 137.4, 137.4, 130.2,130.1, 130.0, 130.0, 129.8, 129.8, 128.5, 128.3, 128.2, 127.2, 73.3,73.3, 63.9, 61.9, 61.7, 54.8, 54.2, 54.1, 47.6, 47.2, 40.9, 40.9, 40.8,33.8, 33.2, 32.2, 31.3, 31.2, 31.1, 30.8, 30.2, 30.1, 28.7, 28.7, 28.7,25.3, 23.9, 21.3, 21.0. Data for S-isomer: R_(f)=0.24 (1:1hexanes/EtOAc). Data for R-isomer: R_(f)=0.38 (1:1 hexanes/EtOAc). ¹HNMR (400 MHz, CDCl₃) δ: 7.34-7.29 (m, 1H), 7.20-7.12 (m, 3H), 7.08 (d,1H, J=7.2 Hz), 6.00 (d, 1H, J=8.8 Hz), 5.33 (d, 1H, J=8.8 Hz), 5.14-5.07(m, 1H), 4.57-4.47 (m, 1H), 4.06-4.02 (m, 1H), 3.28 (t, 1H, J=12.8 Hz),2.85-2.79 (m, 2H), 2.76 (s, 3H), 2.34-2.26 (m, 1H), 2.01-1.90 (m, 2H),1.87-1.73 (m, 6H), 1.47 (s, 9H), 1.35 (s, 3H), 1.30 (d, 3H, J=7.2 Hz),1.25-1.20 (m, 1H), 1.15 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 171.5,170.6, 170.6, 169.3, 137.9, 136.3, 129.4, 129.1, 129.0, 127.5, 126.3,73.0, 62.8, 53.9, 47.8, 46.5, 39.9, 39.8, 33.3, 32.7, 30.6, 30.1, 29.3,28.5, 28.5, 24.6, 19.8. HRMS calcd for C₃₀H₄₄N₄O₅S: 595.2925. found595.2922.

Example 46 Preparation of(4S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide

Same procedure as Example 24 using carbamate (62 mg, 0.108 mmol, 1equiv) and TFA (66 μL, 0.866 mmol, 8 equiv) in DCM (3 mL). Afterstirring for 20 h at 38° C., the solution was concentrated. The productwas eluted through a short plug (˜500 mg) of Silicyle® TMA-chloride ionexchange resin with MeOH to yield product.HCl (54 mg, quantitative) as a1:1 diastereomixture. ¹H NMR (400 MHz, CD₃OD) δ: 7.34-7.27 (m, 2H),7.18-7.06 (m, 7H), 5.54-5.45 (m, 1H), 5.41 (t, 1H, J=8.0 Hz), 5.11-5.06(m, 1H), 5.06-5.01 (m, 1H), 4.77-4.71 (m, 2H), 4.23 (s, 1H), 4.16 (s,1H), 3.97-3.89 (m, 2H) 3.29-3.19 (m, 2H), 2.93-2.84 (m, 2H), 2.78 (dd,4H, J=6.4, 12.8 Hz), 2.68 (s, 6H), 2.32-2.21 (m, 3H), 2.01-1.75 (m,12H), 1.55 (d, 3H, J=7.2 Hz), 1.54-1.50 (m, 2H), 1.47 (d, 3H, J=6.8 Hz),1.40-1.37 (m, 2H), 1.16 (s, 6H), 1.14 (s, 3H), 1.13 (s, 3H); ¹³C NMR(100 MHz, CD₃OD) δ: 172.4, 172.3, 171.8, 171.4, 169.3, 168.9, 138.8,138.5, 137.4, 137.4, 130.1, 130.1, 129.8, 128.3, 127.1, 127.0, 73.4,63.8, 61.8, 58.3, 55.1, 54.4, 40.9, 40.9, 40.7, 33.6, 32.1, 31.8, 31.7,31.3, 31.1, 30.9, 30.2, 30.1, 28.7, 23.9, 21.3, 21.0, 16.3, 16.2. HRMScalcd for C₂₅H₃₇N₄O₃S: 473.2581. found 473.2579.

Example 47 Preparation of(4S,7S,9aS)-4-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)propanamido)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxylicacid

To a solution of amide (142 mg, −0.285 mmol, 1.0 equiv) in MeOH (6 mL)was added 1M NaOH (1 mL). After stirring for 3 h, the methanol wasremoved in vacuo. Then EtOAc (10 mL) and 1 M NaOH (8 mL) were added andan extraction was performed, with the organic layer being discarded. Theaqueous layer was acidified with 3M HCl to pH≦2 and then extracted withDCM (3×5 mL). The organics were dried over sodium sulfate, filtered andconcentrated in vacuo. The resultant oil was purified by flashchromatography on silica gel (1:3 hexanes/EtOAc→DCM→5% MeOH/DCM) toyield the product as a colorless oil (85 mg, 75%). R_(f)=0.17 (7%MeOH/DCM). ¹H NMR (400 MHz, CDCl₃) δ: 7.30 (bs, 1H), 5.22 (m, 1H), 4.77(t, 1H, J=8.0 Hz), 4.52-4.46 (m, 1H), 4.14 (d, 1H, J=12.8 Hz), 3.95 (t,1H, J=12.0 Hz), 2.78 (s, 3H), 2.32-2.18 (m, 2H), 2.13-2.02 (m, 2H),2.00-1.85 (m, 2H), 1.44 (s, 9H), 1.33 (d, 3H, J=7.2 Hz); ¹³C NMR (100MHz, CDCl₃) δ: 171.5, 171.5, 156.2, 156.1, 89.8, 80.8, 80.7, 70.7, 59.7,52.9, 32.7, 30.4, 30.4, 28.4, 28.4, 26.5, 26.5, 14.2. HRMS calcd forC₁₈H₂₉N₃O₇Na: 422.18977. found 422.19015.

Example 48 Preparation of tert-butyl((S)-1-(((4S,7S,9aS)-7-((R)-chroman-4-ylcarbamoyl)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepin-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of carboxylic acid (50 mg, 0.125 mmol, 1.0 equiv),(R)-chroman-4-ylamine.HCl (23 mg, 0.125 mmol, 1.0 equiv), HOBT.xH₂O (21mg, 0.138 mmol, 1.1 equiv) and NMM (41 μL, 0.376 mmol, 3 equiv) in THF(5 mL) at 0° C. was added EDC.HCl (25 mg, 0.131 mmol, 1.05 equiv). After30 min the cold bath was removed. The solution stirred for 14 h and thenwas quenched with saturated aqueous NaHCO₃ (15 mL), extracted with ethylacetate (2×10 mL), dried over sodium sulfate and then concentrated invacuo. The resultant oil was purified by flash chromatography on silicagel (1:3 hexanes/EtOAc) to yield the product (58 mg, 88%). R_(f)=0.11(1:2 hexanes/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 7.16-7.10 (m, 3H), 6.91(d, 1H, J=7.2 Hz), 6.86-6.77 (m, 2H), 5.22 (t, 1H, J=6.0 Hz), 5.12 (q,1H, J=6.8 Hz), 4.68 (dd, 1H, J=6.0, 11.2 Hz), 4.59 (d, 1H, J=7.2 Hz),4.22 (td, 1H, J=2.8, 7.2 Hz), 4.15-4.08 (m, 1H), 4.06-4.01 (m, 1H), 3.92(t, 1H, J=12.4 Hz), 2.74 (s, 3H), 2.41-2.37 (m, 2H), 2.25-2.17 (m, 1H),2.16-2.07 (m, 1H), 2.02 (dd, 1H, J=2.8, 7.2 Hz), 1.95-1.84 (m, 2H),1.61-1.45 (m, 1H), 1.42 (s, 9H), 1.31 (d, 3H, J=7.2 Hz); ¹³C NMR (100MHz, CDCl₃) δ: 171.5, 170.1, 155.0, 129.3, 128.9, 122.3, 120.7, 117.2,90.2, 77.2, 70.6, 63.6, 60.5, 52.6, 43.8, 32.7, 32.5, 30.2, 29.0, 28.4,25.9. HRMS calcd for C₂₇H₃₈N₄O₇Na: 553.26327. found 553.26399.

Example 49 Preparation of(4S,7S,9aS)—N—((R)-chroman-4-yl)-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

To a solution of carbamate (58 mg, 0.109 mmol, 1 equiv) in DCM (2 mL)was added TFA (83 μL, 1.09 mmol, 10 equiv). After stirring for 20 h at32° C., the solution was concentrated. The product was eluted through ashort plug (˜500 mg) of Silicyle® TMA-chloride ion exchange resin withMeOH to yield product.HCl (51 mg, quantitative). ¹H NMR (400 MHz, CD₃OD)δ: 7.33 (d, 1H, J=7.6 Hz), 7.13 (t, 1H, J=8.4 Hz), 6.86 (t, 1H, J=7.2Hz), 6.76 (d, 1H, J=8.0 Hz), 5.39 (dd, 1H, J=3.6, 6.8 Hz), 5.08 (t, 1H,J=6.0 Hz), 4.40 (d, 1H, J=6.8 Hz), 4.26-4.12 (m, 3H), 4.03-3.89 (m, 2H),2.67 (s, 3H), 2.33-2.24 (m, 1H), 2.14-1.97 (m, 6H), 1.81 (dd, 1H, J=2.0,14.0 Hz), 1.58 (d, 3H, J=6.8 Hz); ¹³C NMR (100 MHz, CD₃OD) δ: 172.9,172.2, 169.6, 156.4, 130.5, 130.0, 123.5, 121.6, 117.8, 91.0, 71.3,64.6, 62.3, 58.4, 54.2, 49.0, 44.9, 33.6, 33.3, 31.8, 30.2, 28.0, 16.4.HRMS calcd for C₂₂H₃₁N₄O₅: 431.2289. found 431.2286.

Example 50 Preparation of(4S,7R,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxylicacid

To a solution of amide (105 mg, 0.211 mmol, 1.0 equiv) in MeOH (4 mL)was added 1M NaOH (1 mL). After stirring for 3 h, the methanol wasremoved in vacuo. HPLC analysis of the crude reaction mixture revealedthat the R-isomer didn't react as cleanly as the S-isomer (Example 47).Then DCM (10 mL) and 1 M NaOH (8 mL) were added and an extraction wasperformed, with the organic layer being discarded. The aqueous layer wasacidified with 3M HCl to pH≦2 and then extracted with DCM (3×5 mL). Theorganics were dried over sodium sulfate, filtered and concentrated invacuo. The resultant oil was purified by flash chromatography on silicagel (1:3 hexanes/EtOAc→DCM→5% MeOH/DCM) to yield the product as acolorless oil (22 mg, 26%). R_(f)=0.14 (7% MeOH/DCM). ¹H NMR (400 MHz,CDCl₃) δ: 5.25 (d, 1H, J=6.8 Hz), 4.83 (dd, 1H, J=5.6, 9.6 Hz), 4.65 (d,1H, J=8.8 Hz), 4.14-4.09 (m, 1H), 4.0 (t, 1H, J=12.0 Hz), 2.79 (s, 3H),2.41-2.31 (m, 1H), 2.27-2.11 (m, 2H), 2.06-1.96 (m, 1H), 1.78 (qd, 1H,J=3.6, 12.0 Hz), 1.46 (s, 9H), 1.33 (d, 3H, J=7.6 Hz); ¹³C NMR (100 MHz,CDCl₃) δ: 173.9, 172.0, 171.3, 89.6, 80.9, 70.7, 60.6, 59.8, 53.1, 33.0,32.5, 30.5, 28.5, 26.1, 21.2, 14.3, 14.1. HRMS calcd for C₁₈H₂₉N₃O₇Na:422.18977. found 422.19015.

Example 51 Preparation of tert-butyl((S)-1-(((4S,7R,9aS)-7-((R)-chroman-4-ylcarbamoyl)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepin-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of carboxylic acid (21 mg, 0.0053 mmol, 1.0 equiv),(R)-chroman-4-ylamine*HCl (10 mg, 0.0053 mmol, 1.0 equiv), HOBT.xH₂O (9mg, 0.0058 mmol, 1.1 equiv) and NMM (17 μL, 0.0158 mmol, 3 equiv) in THF(3 mL) at 0° C. was added EDC.HCl (11 mg, 0.0055 mmol, 1.05 equiv).After 30 min the cold bath was removed. The solution stirred for 14 hand then was quenched with saturated aqueous NaHCO₃ (10 mL), extractedwith ethyl acetate (2×10 mL), dried over sodium sulfate and thenconcentrated in vacuo. The resultant oil was purified by flashchromatography on silica gel (1:1→1:3 hexanes/EtOAc) to yield theproduct (9 mg, 33%). ¹H NMR (400 MHz, CDCl₃) δ:7.20-7.12 (m, 3H), 6.89(t, 1H, J=7.6 Hz), 6.82 (d, 1H, J=8.4 Hz), 5.23-5.19 (m, 1H), 5.12-5.05(m, 1H), 4.79-4.71 (m, 1H), 4.55 (d, 1H, J=8.0 Hz), 4.26-4.19 (m, 1H),4.15-4.06 (m, 2H), 3.97 (t, 1H, J=12.0 Hz), 2.77 (s, 3H), 2.39-2.26 (m,1H), 2.24-2.13 (m, 2H), 2.07-2.00 (m, 1H), 1.99-1.91 (m, 2H), 1.80-1.70(m, 2H), 1.44 (s, 9H), 1.34 (d, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CDCl₃)δ:172.3, 171.1, 169.9, 155.2, 129.4, 129.3, 122.0, 120.9, 117.3, 90.1,70.6, 63.4, 61.1, 53.1, 43.8, 33.4, 32.7, 32.1, 29.8, 29.1, 28.5, 25.6,22.8, 14.3. HRMS calcd for C₂₇H₃₈N₄O₇Na: 553.26327. found 553.26399.

Example 52 Preparation of(4S,7R,9aS)—N—((R)-chroman-4-yl)-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

To a solution of carbamate (58 mg, 0.109 mmol, 1 equiv) in DCM (2 mL)was added TFA (83 L, 1.09 mmol, 10 equiv). After stirring for 20 h at32° C., the solution was concentrated to yield product.TFA (51 mg,quantitative). ¹H NMR (400 MHz, CD₃OD) δ: 8.43 (d, 1H, J=8.0 Hz),7.15-7.09 (m, 2H), 6.85 (t, 1H, J=8.0 Hz), 6.78-6.73 (m, 1H), 5.40 (d,2H, J=5.6 Hz), 5.10-5.04 (m, 1H), 4.99 (dd, 1H, J=2.4, 11.2 Hz), 4.53(d, 1H, J=9.2 Hz), 4.21 (t, 2H, J=5.2 Hz), 4.14 (dt, 1H, J=3.2, 13.2Hz), 4.05-3.96 (m, 1H), 3.91 (q, 1H, J=7.2 Hz), 2.67 (s, 3H), 2.44-2.31(m, 1H), 2.30-2.18 (m, 1H), 2.16-2.07 (m, 1H), 2.04-1.95 (m, 3H),1.93-1.81 (m, 2H), 1.52 (d, 3H, J=6.8 Hz); ¹³C NMR (100 MHz, CD₃OD) δ:173.5, 172.7, 169.3, 156.5, 130.2, 129.9, 123.5, 121.6, 117.9, 91.1,71.2, 64.6, 62.3, 58.3, 54.4, 44.9, 34.0, 33.3, 31.8, 30.1, 28.2, 16.4.HRMS calcd for C₂₂H₃₀N₄O₅Na: 453.21084. found 453.21280.

Example 53 Preparation of (S)-ethyl2-((S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanamido)-3-(1H-indol-3-yl)propanoate

To a solution of tryptophan derivative (600 mg, 2.23 mmol, 1.0 equiv),Boc-N-Me-Ala-OH (530 mg, 2.23 mmol, 1.0 equiv), HOBT.xH₂O (376 mg, 2.46mmol, 1.1 equiv) and NMM (736 μL, 6.70 mmol, 3 equiv) in THF (15 mL) at0° C. was added EDC-HCl (449 mg, 2.34 mmol, 1.05 equiv). After 30 minthe cold bath was removed. The solution was stirred for 14 h and thenquenched with saturated aqueous NaHCO₃ (20 mL), extracted with ethylacetate (2×20 mL), dried over sodium sulfate and then concentrated invacuo. The resultant oil was purified by flash chromatography on silicagel (3:1→1:1 hexanes/EtOAc) to yield the product (790 mg, 79%). LCMScalcd for M+H: 452.22. found 452.22.

Example 54 Preparation of(S)-2-((S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanamido)-3-(1H-indol-3-yl)propanoicacid (88)

To a solution of ester (790 mg, 1.75 mmol, 1.0 equiv) in THF (12 mL) andH₂O (3 mL) was added LiOH (84 mg, 3.50 mmol, 2 equiv). After stirringfor 3 h, Et₂O (10 mL) and 1 M NaOH (8 mL) were added and an extractionwas performed, with the organic layer being discarded. The aqueous layerwas acidified with 3M HCl to pH≦2 and then extracted with DCM (3×8 mL).The combined organics were dried over sodium sulfate, filtered andconcentrated in vacuo. The resultant oil was purified by flashchromatography on silica gel (DCM→5% MeOH/DCM) to yield the product as acolorless oil (574 mg, 78%). LCMS calcd for M+H: 424.19. found 424.18.

Example 55 Preparation of benzyl((2S)-1-(((2S)-1-((5,5-dimethoxy-1-oxo-1-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)pentan-2-yl)amino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A mixture of carboxylic acid (104 mg, 0.246 mmol, 1.0 equiv), aldehyde(34 mg, 0.258 mmol, 1.0 equiv), isocyanide (39 mg, 0.246 mmol, 1.0equiv) and 7 M ammonia in MeOH (70 μL, 0.491 mmol, 2.0 equiv) in TFE (3mL) was stirred under microwave irradiation at a set temperature of 80°C. for 20 min. The mixture was then transferred to a round bottom flaskand concentrated in vacuo, then 1 M NaOH (15 mL) was added and themixture was extracted with DCM (3×7 mL). The organics were dried overNa₂SO₄, filtered and concentrated in vacuo. The resultant oil was usedwithout further purification in the next step. LCMS calcd for M+H:712.37. found 712.34.

Example 56 Preparation of benzylmethyl((S)-1-oxo-1-(((3S,6S,12bR)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,5,6,7,12,12b-octahydropyrrolo[1′,2′:1,2]azepino[3,4-b]indol-6-yl)amino)propan-2-yl)carbamate

To a solution of dimethyl acetal (166 mg, 0.233 mmol, 1 equiv) in DCM (4mL) was added TFA (143 μL, 1.87 mmol, 8 equiv). After stirring for 20 hat 23° C., the solution was concentrated and then purified by flashchromatography on silica gel (1:1→1:2 hexanes/EtOAc) to yield S-isomer(18 mg, 11%), R-isomer (38 mg, 24%) and a mixture of the two isomers (10mg, 6%). LCMS calcd for M+H: 648.32. found 648.30.

Example 57 Preparation of(3S,6S,12bR)-6-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,5,6,7,12,12b-octahydropyrrolo[1′,2′:1,2]azepino[3,4-b]indole-3-carboxamide

To a solution of carbamate (16 mg, 0.0247 mmol, 1.0 equiv) in methanol(4 mL) was added 10 wt % Pd-C (5 mg). A balloon of H₂ was applied for 16h, then the mixture was filtered through Celite with DCM andconcentrated in vacuo. The resultant oil was purified by preparativescale HPLC to yield the product (6 mg, 43%). LCMS calcd for M+H: 514.28.found 514.28.

Example 58 Preparation of tert-butyl((S)-1-(((4S,7S,9aS)-1,1-dioxido-5-oxo-7-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of sulfide (48 mg, 0.0881 mmol, 1.0 equiv) in DCM (4 mL)at −5° C. was added mCPBA (75% purity, 45 mg, 0.194, 2.2 equiv). After10 minutes the cold bath was removed and the reaction stirred at 23° C.for 3 h, then concentrated. The crude product was purified by flashchromatography on silica gel (3:1→1:1→1:2 hexanes/EtOAc) to yieldS-isomer (15 mg, 21%) and R-isomer (32 mg, 46%). LCMS calcd for M+H:577.27. found 577.29.

Example 59 Preparation of(4S,7S,9aS)-4-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide1,1-dioxide

To a solution of carbamate (15 mg, 0.026 mmol, 1 equiv) in DCM (2 mL)was added TFA (16 μL, 0.208 mmol, 8 equiv). After stirring for 20 h at32° C., the solution was concentrated to yield product.TFA (15 mg,quantitative). LCMS calcd for M+H: 477.22. found 477.23.

Example 60 Preparation ofN,N′-(disulfanediylbis(2,1-phenylene))diformamide

The disulfide was prepared according to the established literatureprocedure; see Hyvl, J., Srogl, J. Eur. J. Org. Chem. 2010, 2849-2851.

Example 61 Preparation of 1,2-bis(2-isocyanophenyl)disulfane

To a solution of formamide (2.41 g, 7.92 mmol, 1.0 equiv) in DCM (40 mL)at 0° C. was added Et₃N (5.60 mL, 40.4 mmol, 5.1 equiv) followed byphosphorus oxychloride (1.09 mL, 11.9 mmol, 1.5 equiv). The mixture waswarmed to 23° C. and stirred for 2 h, at which time it was poured intosaturated NaHCO₃ (200 mL) and extracted with DCM (2×100 mL). Theorganics were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresultant oil was purified by flash chromatography on silica gel (5:1hexanes/EtOAc) to yield the product (980 mg, 46%) which was stored at 0°C. R_(f)=0.38 (5:1 hexanes/EtOAc). LCMS calcd for M+H: 269.02. found269.01.

Example 62 Preparation of(4S,4′S,9aS,9a′S)—N,N′-(disulfanediylbis(2,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide)

Same procedure as Example 24 with Boc-N-HSer-OH (159 mg, 0.725 mmol, 2.0equiv), aldehyde (122 mg, 0.762 mmol, 2.1 equiv), isocyanide (97 mg,0.363 mmol, 1.0 equiv) and 7 M ammonia in MeOH (207 μL, 1.45 mmol, 4.0equiv) in TFE (5 mL). The resultant oil was combined with TFA (302 μL,3.95 mmol, 16 equiv) in DCM (5 mL) and stirred at 40° C. for 14 h. Themixture was concentrated in vacuo, then partially purified by flashchromatography on basic alumina (3:1 hexanes/EtOAc→DCM→7% MeOH/DCM), toyield semi-pure product. LCMS calcd for M+H: 697.28. found 697.28.

Example 63 Preparation of(S,4S,4′S,9aS,9a′S)—N,N′-(disulfanediylbis(2,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide)

Same procedure as Example 25 using bis-amine (69 mg, 0.099 mmol, 1.0equiv), Boc-N-Me-Ala-OH (40 mg, 0.198 mmol, 2.0 equiv), HOBT.xH₂O (33mg, 0.218 mmol, 2.2 equiv), NMM (65 μL, 0.594 mmol, 6 equiv) and EDC.HCl(40 mg, 0.208 mmol, 2.1 equiv) in THF (5 mL). The resultant oil waspurified by flash chromatography on silica gel (3:1→1:1→1:3hexanes/EtOAc) to yield the product (32 mg, overall yield notdetermined). LCMS calcd for M+H: 1067.49. found 1067.60.

Example 64 Preparation of methyl(S,4S,4′S,9aS,9a′S)—N,N′-(disulfanediylbis(2,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrol[2,1-b][1,3]oxazepine-7-carboxamide)

To a solution of carbamate (10 mg, 9.37 μmol, 1 equiv) in DCM (2 mL) wasadded TFA (7 μL, 93.7 μmol, 10 equiv). The mixture was stirred for 16 h,then concentrated in vacuo to give the product.TFA (9.5 mg, 95%). LCMScalcd for [M+CF₃CO₂H]/2+Na: 570.18. found 570.25.

Example 65 Preparation of(4S,10aS)-4-amino-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxamide

A mixture of Boc-N-HCys(Trt)-OH (250 mg, 0.523 mmol, 1.0 equiv),aldehyde (80 mg, 0.550 mmol, 1.05 equiv), isocyanide (82 mg, 0.523 mmol,1.0 equiv) and 7 M ammonia in MeOH (150 μL, 1.05 mmol, 2.0 equiv) in TFE(4 mL) was stirred under microwave irradiation at a set temperature of100° C. for 20 min. The mixture was then transferred to a round bottomflask and concentrated in vacuo, then 1 M NaOH (15 mL) was added and themixture was extracted with DCM (3×7 mL). The combined organics weredried over Na₂SO₄, filtered and concentrated in vacuo. The resultant oilwas combined with TFA (401 μL, 5.23 mmol, 10 equiv) in DCM (5 mL) andstirred at 55° C. for 14 h. The mixture was concentrated in vacuo, thenpartially purified by flash chromatography on basic alumina (3:1hexanes/EtOAc→DCM→7% MeOH/DCM), to yield semi-pure product. LCMS calcdfor M+H: 374.19. found 374.21.

Example 66 Preparation of tert-butylmethyl((2S)-1-oxo-1-(((4S,10aS)-5-oxo-7-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)amino)propan-2-yl)carbamate

Same procedure as Example 25 using amine (156 mg, 0.418 mmol, 1.0equiv), Boc-N-Me-Ala-OH (85 mg, 0.418 mmol, 1.0 equiv), HOBT.xH₂O (70mg, 0.459 mmol, 1.1 equiv), NMM (138 μL, 1.25 mmol, 3 equiv) and EDC.HCl(84 mg, 0.439 mmol, 1.05 equiv) in THF (6 mL). The resultant oil waspurified by flash chromatography on silica gel (3:1→2:1→1:1→1:3hexanes/EtOAc) to yield, after 3 steps, the product (102 mg, 43%overall). LCMS calcd for M+H: 559.30. found 559.32.

Example 67 Preparation of(4S,10aS)-4-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxamide

To a solution of carbamate (41 mg, 0.0734 mmol, 1 equiv) in DCM (2 mL)was added TFA (56 μL, 0.734 mmol, 10 equiv). The mixture was stirred for16 h, then concentrated in vacuo to give the product.TFA (42 mg,quantitative). LCMS calcd for M+H: 459.24. found 459.28.

Example 68 Preparation of tert-butyl((6S,9aS)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)hexahydro-2H-oxazolo[2,3-b][1,3]oxazepin-6-yl)carbamate

A mixture of Boc-N-HSer-OH (150 mg, 0.684 mmol, 1.0 equiv),glycolaldehyde dimer (41 mg, 0.342 mmol, 0.5 equiv), isocyanide (108 mg,0.684 mmol, 1.0 equiv) and 7 M ammonia in MeOH (293 μL, 2.05 mmol, 3.0equiv) in TFE (4 mL) was stirred under microwave irradiation at a settemperature of 80° C. for 20 min. The mixture was then transferred to around bottom flask and concentrated in vacuo, then 1 M NaOH (15 mL) wasadded and the mixture was extracted with DCM (3×7 mL). The organics weredried over Na₂SO₄, filtered and concentrated in vacuo. The resultant oilwas combined with trimethyl orthoformate (89 μL, 0.808 mmol, 2 equiv)and TsOH.H₂O (23 mg, 0.121 mmol, 0.3 equiv) in PhH (5 mL) and stirred at90° C. for 10 h. The mixture was concentrated in vacuo and the crudeproduct will be processed as described in preceding examples. LCMS calcdfor M+H: 446.23. found 446.23.

Example 69 Preparation of(6S,11bR)-6-amino-10-hydroxy-2,2-dimethyl-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamide

Same procedure as Example 24 with Boc-Tyr-OH (346 mg, 1.23 mmol, 1.0equiv), aldehyde (197 mg, 1.23 mmol, 1.0 equiv), isocyanide (193 mg,1.23 mmol, 1.0 equiv) and 7 M ammonia in MeOH (351 μL, 2.46 mmol, 2.0equiv) in TFE (4 mL). The resultant oil was combined with TFA (575 μL,7.51 mmol, 8 equiv) in DCM (5 mL) and stirred at 35° C. for 14 h. Themixture was concentrated in vacuo and the crude product used withoutfurther purification in the next step.

Example 70 Preparation of tert-butyl((2S)-1-(((6S,11bR)-10-hydroxy-2,2-dimethyl-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Same procedure as Example 25 using crude amine (406 mg, 0.939 mmol, 1.0equiv), Boc-N-Me-Ala-OH (191 mg, 0.939 mmol, 1.0 equiv), HOBT.xH₂O (158mg, 1.03 mmol, 1.1 equiv), NMM (310 μL, 2.82 mmol, 3 equiv and EDC.HCl(189 mg, 0.986 mmol, 1.05 equiv) in THF (10 mL). The resultant oil waspurified by flash chromatography on silica gel (3:1→1:1→1:3hexanes/EtOAc with <5% DCM in all eluant to dissolve) to yield, after 3steps the unseparated diastereomixture (250 mg, slightly impure). LCMScalcd for M+H: 619.35. found 619.16.

Example 71 Preparation of(6S,11bR)-10-hydroxy-2,2-dimethyl-6-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamide

To a solution of carbamate (47 mg, 0.0760 mmol, 1 equiv) in DCM (2 mL)was added TFA (47 μL, 0.608 mmol, 8 equiv). The mixture was stirred for16 h at 40° C., then concentrated in vacuo to give the product.TFA (42mg, quantitative). The product was purified by reverse phase HPLC. LCMScalcd for M+H: 519.30. found 519.07.

Example 72 Preparation of(4S,9aR)-4-amino-8,8-dimethyl-2,5-dioxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydro-1H-pyrrolo[1,2-a][1,3]diazepine-7-carboxamide

Same procedure as Example 24 with Boc-Asn-OH (290 mg, 1.25 mmol, 1.0equiv), aldehyde (200 mg, 1.25 mmol, 1.0 equiv), isocyanide (196 mg,1.25 mmol, 1.0 equiv) and 7 M ammonia in MeOH (357 μL, 2.50 mmol, 2.0equiv) in TFE (4 mL). The resultant oil was combined with TFA (635 μL,8.30 mmol, 8 equiv) in DCM (5 mL) and stirred at 35° C. for 14 h. Themixture was concentrated in vacuo and the crude product used withoutfurther purification in the next step.

Example 73 Preparation of tert-butyl((2S)-1-(((4S,9aR)-8,8-dimethyl-2,5-dioxo-7-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydro-1H-pyrrolo[1,2-a][1,3]diazepin-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Same procedure as Example 25 using crude amine (398 mg, 1.03 mmol, 1.0equiv), Boc-N-Me-Ala-OH (210 mg, 1.03 mmol, 1.0 equiv), HOBT.xH₂O (174mg, 1.14 mmol, 1.1 equiv), NMM (341 μL, 3.11 mmol, 3 equiv and EDC.HCl(208 mg, 1.09 mmol, 1.05 equiv) in THF (10 mL). The resultant oil waspurified by flash chromatography on silica gel (1:1→1:3hexanes/EtOAc→DCM→3:1 DCM/EtOAc→EtOAc) to yield, after 3 steps theunseparated diastereomixture (300 mg, slightly impure). LCMS calcd forM+H: 570.33. found 570.14.

Example 74 Preparation of(4S,9aR)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-2,5-dioxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydro-1H-pyrrolo[1,2-a][1,3]diazepine-7-carboxamide

To a solution of carbamate (58 mg, 0.102 mmol, 1 equiv) in DCM (2 mL)was added TFA (62 μL, 0.814 mmol, 8 equiv). The mixture was stirred for16 h at 23° C., then concentrated in vacuo to give the product.TFA,which was purified by reverse phase HPLC to give 17 mg of a polar isomerand 7 mg of a less polar isomer. LCMS calcd for M+H: 470.28. found470.36.

Example 75 Preparation of(6S,11bR)-6-amino-9-hydroxy-2,2-dimethyl-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamideand(6S,11bR)-6-amino-11-hydroxy-2,2-dimethyl-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamide

Same procedure as Example 24 with Boc-m-Tyr-OH (306 mg, 1.09 mmol, 1.0equiv), aldehyde (192 mg, 1.20 mmol, 1.0 equiv), isocyanide (171 mg,1.09 mmol, 1.0 equiv) and 7 M ammonia in MeOH (311 μL, 2.18 mmol, 2.0equiv) in TFE (4 mL). The resultant oil was combined with TFA (625 μL,8.16 mmol, 8 equiv) in DCM (5 mL) and stirred at 23° C. for 14 h. Themixture was concentrated in vacuo and the crude product used withoutfurther purification in the next step.

Example 76 Preparation of tert-butyl((2S)-1-(((6S,11bR)-9-hydroxy-2,2-dimethyl-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamateand tert-butyl((2S)-1-(((6S,11bR)-11-hydroxy-2,2-dimethyl-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Same procedure as Example 25 using crude amine (442 mg, 1.02 mmol, 1.0equiv), Boc-N-Me-Ala-OH (207 mg, 1.02 mmol, 1.0 equiv), HOBT.xH₂O (172mg, 1.12 mmol, 1.1 equiv), NMM (337 μL, 3.06 mmol, 3 equiv and EDC.HCl(205 mg, 1.07 mmol, 1.05 equiv) in THF (10 mL). The resultant oil waspurified by flash chromatography on silica gel (3:1-1:1→1:3hexanes/EtOAc→7% MeOH/DCM, all eluant with <5% DCM to dissolve) toyield, after 3 steps three product-containing fractions (most polar: 253mg, medium polarity: 112 mg, least polar: 92 mg). LCMS calcd for M+H:619.35. found 619.45.

Example 77 Preparation of(6S,11bR)-9-hydroxy-2,2-dimethyl-6-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamideand(6S,11bR)-11-hydroxy-2,2-dimethyl-6-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamide

Each fraction of Example 77 was run separately. To a solution ofcarbamate (253 mg most polar isomer, 112 mg medium polarity isomer, 92mg least polar isomer) in DCM (2 mL) was added TFA (250, 111, 91 μL,respectively, 8 equiv). The mixture was stirred for 16 h at 40° C., thenconcentrated in vacuo to give the product.TFA, which was purified byreverse phase HPLC to give 151 mg of the most polar isomer, 55 mg of themedium polarity isomer and 19 mg of the least polar isomer. LCMS calcdfor M+H: 519.30. found 519.41.

Example 78 Preparation of two regioisomers:(6S,11bR)-6-amino-9,10-dihydroxy-2,2-dimethyl-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamideand(6S,11bR)-6-amino-10,11-dihydroxy-2,2-dimethyl-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamide

Same procedure as Example 24 with Boc-3,4-dihydroxy-L-phenylalanine (288mg, 0.967 mmol, 1.0 equiv), aldehyde (155 mg, 0.967 mmol, 1.0 equiv),isocyanide (152 mg, 0.967 mmol, 1.0 equiv) and 7 M ammonia in MeOH (276μL, 1.93 mmol, 2.0 equiv) in TFE (4 mL). The resultant oil was combinedwith TFA (369 μL, 4.82 mmol, 8 equiv) in DCM (5 mL) and stirred at 35°C. for 14 h. The mixture was concentrated in vacuo and the crude productused without further purification in the next step.

Example 79 Preparation of two regioisomers: tert-butyl((2S)-1-(((6S,11bR)-9,10-dihydroxy-2,2-dimethyl-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamateand tert-butyl((2S)-1-(((6S,11bR)-10,11-dihydroxy-2,2-dimethyl-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

Same procedure as Example 25 using crude amine (339 mg, 0.602 mmol, 1.0equiv), Boc-N-Me-Ala-OH (122 mg, 0.602 mmol, 1.0 equiv), HOBT.xH₂O (101mg, 0.662 mmol, 1.1 equiv), NMM (198 L, 1.80 mmol, 3 equiv and EDC.HCl(121 mg, 0.632 mmol, 1.05 equiv) in THF (10 mL). The resultant oil wasnot purified (to avoid degradation) and used crude in the next step.LCMS calcd for M+H: 635.34. found 635.16.

Example 80 Preparation of two regioisomers:(6S,11bR)-9,10-dihydroxy-2,2-dimethyl-6-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamideand(6S,11bR)-10,11-dihydroxy-2,2-dimethyl-6-((S)-2-(methylamino)propanamido)-5-oxo-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyrrolo[1,2-a]azepine-3-carboxamide

To a solution of carbamate (54 mg, 0.00851 mmol, 1 equiv) in DCM (2 mL)was added TFA (52 μL, 0.681 mmol, 8 equiv). The mixture was stirred for16 h at 25° C., then concentrated in vacuo to give the product.TFA,which was purified by reverse phase HPLC to give 3.7 mg of a more polarisomer and 7 mg of a less polar isomer. LCMS calcd for M+H: 535.29.found 535.17.

BIOLOGY EXAMPLES Example B-1

5000 PPC-1 cells were plated and grown overnight. Compounds were platedand 4 hrs later, TRAIL was added to half of the plate while RPMI wasadded to the other half of the plate as a control. Plates were return tothe incubator for 24 hrs. Plates were removed from the incubator andplaced on the bench for 30 min and then 25 uL of Cell Titer Glo wereadded per well. Plates were placed on a rocker and then read on aluminometer. 5000 MDA-MB-231 cells were plated per well. Compound wasadded and 4 hrs later, TRAIL was added at 5 ng/mL; RPMI was added for aminus TRAIL control. Plates were incubated an additional 24 hrs, removedto the bench for 30 min. and then 25 uL of cell titer glo was added perwell. Plates were placed on a rocker and read on a luminometer. Datawere fit using PRISM.

Table B-1 below shows assay data for certain compounds described herein.

TABLE B-1 MDA- XIAP XIAP ML- MB- PPC-1 PPC-1 BIR1/2 BIR3 IAP 231 (TRAIL)(TNFα) Compd Ki Ki Ki LD50 LD50 LD50 Structure No. (μM) (μM) (μM) (μM)(μM) (μM)

 1

 2

 3 C B

 4 C B

 5 C B

 6 C B

 7 C B

 8 C B

 9 C A

10 C A A

11 C B

12 C A A A A A

13 A A

14 C A A

15 C B

16 B A

17 A A

18 C B

19 C B

20 C A

21 C A

22 C B

23 C B

24 C A A A A A

25 A A

26 A A A A A A

27 C A A A A

28 C B

29 C C

30 C B

31 A A

32 C A A A A A

33 C A A A A

34 C A A A A

35 A A A A A

36 C A A

37 C A

38 C B

39 C B

40 A A

41 A A

42 A A A

43 A A

44 A A A

45 A A

46 C A A

47 A A A

KEY: A = ≦25 micromolar; B >25 and ≦50 micromolar; C >50 micromolar

Example B-2 Clinical Trial for Leukemia

Study Type: Interventional

Endpoint Classification: Safety/Efficacy Study

Intervention Model: Single Group Assignment

Masking: Open Label

Primary Purpose: Treatment

Purpose

The purpose of this study is to determine how well a compound of FormulaA, Formula B, Formula C, Formula D, Formula E, Formula F, or Formula G,or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, works to treat relapsed or refractory acute myeloid leukemia,acute lymphoblastic leukemia, myelodysplastic syndrome, or chronicmyelogenous leukemia in blastic phase.

Intervention

Patients are administered 35 mg/kg of a compound of Formula A, FormulaB, Formula C, Formula D, Formula E, Formula F, or Formula G, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, by IV infusion, once every two weeks for 14 weeks.

Outcome Measures

The primary outcome measure is the patient's response to a compound ofFormula A, Formula B, Formula C, Formula D, Formula E, Formula F, orFormula G, or pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof, as first-line treatment in patients with relapsedor refractory acute myeloid leukemia, acute lymphoblastic leukemia,myelodysplastic syndrome, or chronic myelogenous leukemia in blasticphase.

The secondary outcome measure is (a) to evaluate the side-effects of acompound of Formula A, Formula B, Formula C, Formula D, Formula E,Formula F, or Formula G, or pharmaceutically acceptable salt, N-oxide,racemate or stereoisomer thereof; (b) the efficacy of a compound ofFormula A, Formula B, Formula C, Formula D, Formula E, Formula F, orFormula G, or pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof, on relapsed or refractory acute myeloid leukemia,acute lymphoblastic leukemia, myelodysplastic syndrome, or chronicmyelogenous leukemia in blastic phase; and (c) to evaluate quality oflife in patients following treatment.

Detailed Description

Patients will be given a compound of Formula A, Formula B, Formula C,Formula D, Formula E, Formula F, or Formula G, or pharmaceuticallyacceptable salt, N-oxide, racemate or stereoisomer thereof,intravenously once, every two weeks for 14 weeks. Prior to eachinjection of a compound of Formula A, Formula B, Formula C, Formula D,Formula E, Formula F, or Formula G, or pharmaceutically acceptable salt,N-oxide, racemate or stereoisomer thereof, a physical exam, blood workand assessment of any side effects will be performed. Every 5 weeks thepatient's cancer will be re-evaluated to determine whether the treatmentis working. Participation in this study will last at least 14 weeks,however patients may remain on the study as long as there is no diseaseprogression, and they are able to tolerate the study drug without severeside effects.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Male or female

Disease Characteristics

Diagnosis of 1 of the following: Acute myeloid leukemia, Acutelymphoblastic leukemia, Myelodysplastic syndromes (Refractory anemiawith excess blasts [RAEB], RAEB in transformation, Chronicmyelomonocytic leukemia in transformation with ≧10% peripheralblood/bone marrow blasts), Chronic myelogenous leukemia in blastic phase

Disease status must meet 1 of the following criteria: primary resistantdisease (i.e., failed to achieve a complete response [CR] to a priorstandard induction regimen), or relapsed disease after achieving a CR

Documented failure to most recent cytotoxic regimen

No other potentially curative options

No known CNS disease

Patient Characteristics

Over 18

Performance status: ECOG 0-2

Life expectancy: Not specified

Hematopoietic: Not specified

Hepatic: SGOT or SGPT<3 times upper limit of normal*; Bilirubin≦2 mg/dL*NOTE: *Unless due to organ leukemic involvement

Renal: Creatinine≦2 mg/dL (unless due to organ leukemic involvement)

Cardiovascular: no symptomatic congestive heart failure; no unstableangina pectoris; no cardiac arrhythmia

Not pregnant or nursing

Negative pregnancy test

Fertile patients must use effective contraception

No ongoing or active infection

No psychiatric illness or social situation that would preclude studycompliance

No AIDS-defining disease—HIV positive allowed if CD4 counts normal

No other concurrent uncontrolled illness

No concurrent prophylactic hematopoietic colony-stimulating factors

Chemotherapy: More than 2 weeks since prior cytotoxic chemotherapy(except hydroxyurea) and recovered

Endocrine therapy: Not specified

Radiotherapy: More than 2 weeks since prior radiotherapy and recovered

Surgery: Not specified

No concurrent combination antiretroviral therapy for HIV-positivepatients

No other concurrent investigational agents

No other concurrent anticancer agents or therapies

Example B-3 Clinical Trial for Renal Cancer

Study Type: Interventional

Study Design: Endpoint Classification: Safety/Efficacy Study

Intervention Model: Single Group Assignment

Masking: Open Label

Primary Purpose: Treatment

Purpose

The purpose of this study is to determine overall survival of patientswith renal cancer after treatment with a compound of Formula A, FormulaB, Formula C, Formula D, Formula E, Formula F, or Formula G, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof.

Intervention

Patients are orally administered a compound of Formula A, Formula B,Formula C, Formula D, Formula E, Formula F, or Formula G, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, at 15 mg/kg, every 4 days for 12 weeks.

Every week a physical exam, blood work and assessment of any sideeffects will be performed. Every 4 weeks the patient's cancer will bere-evaluated to determine whether the treatment is working.

Participation in this study will last until patient death or as long asthere is no disease progression, and they are able to tolerate the studydrug without severe side effects.

Outcome Measures

Primary Outcome Measures: The primary outcome measure is the patient'sresponse to a compound of Formula A, Formula B, Formula C, Formula D,Formula E, Formula F, or Formula G, or pharmaceutically acceptable salt,N-oxide, racemate or stereoisomer thereof.

Secondary Outcome Measures: The second outcome measures are (a) anevaluation of the side-effects of a compound of Formula A, Formula B,Formula C, Formula D, Formula E, Formula F, or Formula G, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof; (b) an evaluation of the proportion of patients that havecomplete or partial response or stable disease at 6 months; and (c) anevaluation of the time to progression and overall survival of patientstreated with a compound of Formula A, Formula B, Formula C, Formula D,Formula E, Formula F, or Formula G, or pharmaceutically acceptable salt,N-oxide, racemate or stereoisomer thereof.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Male or female

Inclusion Criteria

Patients must have histologically confirmed metastatic or unresectablerenal cell carcinoma. Predominant clear cell component is required. Purepapillary and chromophobe renal cell carcinoma, collecting duct tumorsand transitional cell carcinoma are not eligible.

Patients must have at least one measurable site of disease according toRECIST criteria that has not been previously irradiated. If the patienthas had previous radiation to the marker lesion(s), there must beevidence of progression since radiation.

Patients must have metastatic disease which has progressed on or within6 months of stopping treatment with VEGFR receptor tyrosine kinaseinhibitors. Previous therapy with bevacizumab, interleukin 2, orinterferon alpha is also permitted.

Ability to provide written informed consent obtained prior toparticipation in the study and any related procedures being performed.

Patients must meet the following laboratory criteria: serum albumin≧3g/dL; AST/SGOT and ALT/SGPT≦2.5×upper limit of normal (ULN); serumbilirubin≦1.5×ULN; serum creatinine≦1.5×ULN or 24 hour creatinineclearance≧50 ml/min; serum potassium≧LLN; serum phosphorus≧LLN; serumtotal calcium (corrected for serum albumin) or serum ionizedcalcium≧LLN; serum magnesium≧LLN; TSH and free T4 within normal limits(WNL) (patients may be on thyroid hormone replacement); adequate bonemarrow function as shown by: ANC≧1.5×10 to the 9th power/L,Platelets≧100×10 to the 9th power, Hb≧9 g/dL; INR≦1.3; fasting serumcholesterol≦300 mg/dL OR≦7.75 mmol/L AND fasting triglycerides≦2.5×ULN.

Baseline MUGA or ECHO must demonstrate LVEF≧the lower limit of theinstitutional normal.

ECOG Performance Status of ≦2

Exclusion Criteria

Patients currently receiving anticancer therapy within 4 weeks of thestudy drug (including chemotherapy, radiation therapy, antibody therapy,etc.)

Patients who have had major surgery or significant traumatic injurywithin 4 weeks of start of study drug patients who have not recoveredfrom the side effects of any major surgery (defined as requiring generalanesthesia) or patients that may require major surgery during the courseof the study

Prior treatment with any investigational drug within the preceding 4weeks

Patients receiving chronic, systemic treatment with corticosteroids oranother immunosuppressive agent. Topical or inhaled corticosteroids areallowed

Patients should not receive immunization with attenuated live vaccineswithin one week of study entry or during study period

Uncontrolled brain or leptomeningeal metastases, including patients whocontinue to require glucocorticosteroids for brain or leptomeningealmetastases

Other malignancies within the past 3 years except for adequately treatedcarcinoma of the cervix or basal or squamous cell carcinomas of the skin

Patients who have any severe and/or uncontrolled medical conditions orother conditions that could affect their participation in the study suchas: symptomatic congestive heart failure of New York Heart AssociationClass III or IV; unstable angina pectoris, symptomatic congestive heartfailure, myocardial infarction within 6 months of study drug, seriousuncontrolled cardiac arrhythmia or any other clinically significantheart disease; concomitant use of drugs with a risk of causing torsadesde pointes; severely impaired lung function (O2 saturation 90% or lessat rest on room air); uncontrolled diabetes as defined be fasting serumglucose>1.5 ULN; active (acute or chronic) or uncontrolled severeinfections; liver disease such as cirrhosis, chronic active hepatitis orchronic persistent hepatitis

A known history of HIV seropositivity

Impairment of gastrointestinal (GI) function or GI disease

Patients with an active, bleeding diathesis

Female patients who are pregnant or breast feeding or adults ofreproductive potential who are not using effective birth controlmethods. If barrier contraceptives are used, these must be continuedthroughout the trial by both sexes. Hormonal contraceptives are notacceptable as a sole method of contraception.

History of non-compliance to medical regimens

Patients unwilling to or unable to comply with the protocol

Example B-4 Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula A, Formula B, Formula C, Formula D, Formula E,Formula F, or Formula G, or pharmaceutically acceptable salt, N-oxide,racemate or stereoisomer thereof, is dissolved in 2% HPMC, 1% Tween 80in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL. The mixture isincorporated into a dosage unit form suitable for administration byinjection.

Example B-5 Oral Composition

To prepare a pharmaceutical composition for oral delivery, 400 mg of acompound of Formula A, Formula B, Formula C, Formula D, Formula E,Formula F, or Formula G, or pharmaceutically acceptable salt, N-oxide,racemate or stereoisomer thereof, and the following ingredients aremixed intimately and pressed into single scored tablets.

Tablet Formulation Quantity per tablet Ingredient mg compound 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Capsule Formulation Quantity per capsule Ingredient mg compound 200lactose spray dried 148 magnesium stearate 2

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A compound having the structure of Formula B-I,pharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof:

wherein, R¹ is H, or C₁-C₆alkyl; X¹ is selected from S, S(O) and S(O)₂,X² is CR^(2C)R^(2d), and X³ is CR^(2a)R^(2b); W¹ is C(R^(8a))(R^(8b));W² is C(R^(8c))(R^(8d)); R^(2a), R^(2b), R^(2c), R^(2d) areindependently selected from H, C₁-C₆alkyl, and C₁-C₆heteroalkyl, m is 0,1 or 2; —U— is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—, —S(═O)₂NH—,—NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O)₂NH—; R³ is C₁-C₃alkyl,or C₁-C₃fluoroalkyl; R⁴ is —NHR⁵, —N(R⁵)₂, —N⁺(R⁵)₃ or —OR⁵; each R⁵ isindependently selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₃heteroalkyl and —C₁-C₃alkyl-(C₃-C₅cycloalkyl); R⁶ is —NHC(═O)R⁷,—C(═O)NHR⁷, —NHS(═O)₂R⁷, —NHS(═O)₂NHR⁷;—NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,—(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)—C(═O)NHR⁵,—(C₁-C₃alkyl)-NHS(═O)₂R⁷, —(C₁-C₃alkyl)-S(═O)₂NHR⁷;—C₁—C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, or substituted or unsubstitutedheteroaryl; each R⁷ is independently selected from C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or unsubstitutedC₃-C₁₀cycloalkyl, a substituted or unsubstituted C₂-C₁₀heterocycloalkyl,a substituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₆alkyl-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl,—C₁-C₆alkyl-(substituted or unsubstituted aryl),—C₁-C₆alkyl-(substituted or unsubstituted heteroaryl),-(CH₂)_(p)-CH(substituted or unsubstituted aryl)₂,-(CH₂)_(p)-CH(substituted or unsubstituted heteroaryl)₂,—(CH₂)_(p)-CH(substituted or unsubstituted aryl)(substituted orunsubstituted heteroaryl), -(substituted or unsubstitutedaryl)-(substituted or unsubstituted aryl), -(substituted orunsubstituted aryl)-(substituted or unsubstituted heteroaryl),-(substituted or unsubstituted heteroaryl)-(substituted or unsubstitutedaryl), or -(substituted or unsubstituted heteroaryl)-(substituted orunsubstituted heteroaryl); p is 0, 1 or 2; R^(8a), R^(8b), R^(8c), andR^(8d) are independently selected from H, C₁-C₆alkyl,C_(i)-C₆fluoroalkyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and substituted orunsubstituted aryl; or: R^(8a) and R^(8d) are as defined above, andR^(8b) and R^(8c) together form a bond; where each substituted alkyl,heteroalkyl, fused ring, spirocycle, cycloalkyl, heterocycloalkyl, arylor heteroaryl is substituted with 1-3 R⁹; and each R⁹ is independentlyselected from halogen, —OH,—SH, (C═O), CN, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl),—NH(C₁-C₄alkyl)₂, —C(═O)OH, —C(═O)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃,—NH(C₁-C₄alkyl)-OH, —NH(C₁-C₄alkyl)—O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)—NH₂;—O(C₁-C₄alkyl)—NH—(C₁-C₄alkyl), and —O(C₁-C₄alkyl)—N—(C₁-C₄alkyl)₂, ortwo R⁹ together with the atoms to which they are attached form amethylene dioxy or ethylene dioxy ring substituted or unsubstituted withhalogen, —OH, or C₁-C₃alkyl; where each heterocycloalkyl isindependently selected from a monocyclic, fused bicyclic, and bridgedbicyclic ring, where the heterocycloalkyl is partially or fullysaturated and has from 2 to 10 carbons in the ring and heteroatomsselected from nitrogen, oxygen and sulfur, where each heterocycloalkylis independently selected from dihydrothiophen-2(3H)-onyl,imidazolidin-2-onyl, pyrrolidin-2-onyl, dihydrofuran-2(3H)-onyl,1,3-dioxolan-2-onyl, thiazolidinyl, 2,5-dihydro-1H-pyrrolyl,4,5-dihydro-1H-imidazolyl, tetrahydrofuranyl, 4,5-dihydrooxazolyl,oxiranyl, pyrrolidinyl, pyrazolidinyl, tetrahydro-2H-pyranyl,thiomorpholinyl, tetrahydro-2H-thiopyranyl,2,3-dihydrobenzo[b][1,4]dioxinyl, indolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl,2,3-dihydrobenzo[b]thiophenyl, thiochromanyl, piperidinyl, morpholinyl,4H-1,4-thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl,1,3-oxazinan-2-onyl, 7-oxabicyclo[2.2.1]heptanyl,octahydro-1H-quinolizinyl, and 1,3-diazabicyclo[2.2.2]octanyl; whereeach heteroaryl is independently selected from a monocyclic and fusedbicyclic ring, where the heteroaryl is a 5- to 14-membered ring systemcomprising one to thirteen carbon atoms, one to six heteroatoms selectedfrom the group consisting of nitrogen, oxygen, and sulfur.
 2. Thecompound of claim 1, or pharmaceutically acceptable salt, N-oxide,racemate or stereoisomer thereof, having the structure of FormulaB-III-1:

wherein, —U— is —NHC(═O)—, or —C(═O)NH—; R³ is C₁-C₃alkyl; R⁴ is —NHR⁵,—N(R⁵)₂, or —N⁺(R⁵)₃; each R⁵ is independently selected from H,C₁-C₃alkyl, and —C₁-C₃alkyl-(C₃-C₅cycloalkyl); and R^(2a), R^(2b),R^(2c), R^(2d), R^(2e), and R^(2f) are independently H or C₁-C₃ alkyl.3. The compound of any one of claim 1, or pharmaceutically acceptablesalt, N-oxide, racemate or stereoisomer thereof, wherein,

is


4. The compound of claim 3, or pharmaceutically acceptable salt,N-oxide, racemate or stereoisomer thereof, wherein,

is


5. The compound of claim 1, or pharmaceutically acceptable salt,N-oxide, racemate or stereoisomer thereof, having the structure ofFormula B-V-2, or Formula B-VI-2:


6. The compound of claim 1, or pharmaceutically acceptable salt,N-oxide, racemate or stereoisomer thereof, having the structure ofFormula B-XII:

wherein R^(8a) and R^(8b) are independently selected from H andC₁-C₃alkyl.
 7. The compound of claim 6, or pharmaceutically acceptablesalt, N-oxide, racemate or stereoisomer thereof, wherein: X¹ is S orS(O)₂, and X² is CH₂.
 8. The compound of claim 1, or pharmaceuticallyacceptable salt, N-oxide, racemate or stereoisomer thereof, wherein R¹is H or methyl; and R⁶ is —C(═O)NHR⁷.
 9. The compound of claim 1, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, wherein the compound of Formula B-I has the structure ofFormula B-XXII, or pharmaceutically acceptable salt, N-oxide, racemateor stereoisomer thereof:

wherein, W² is C(R^(8c))(R^(8d)); R¹ is H, or C₁-C₆alkyl; X¹ is S, S(O),or S(O)₂; R^(2a) and R^(2b) are independently selected from H,C₁-C₆alkyl; R³ is C₁-C₃alkyl, or C₁-C₃fluoroalkyl; each R⁵ isindependently selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₃heteroalkyl and —C₁-C₃alkyl-(C₃-C₅cycloalkyl); each R⁷ isindependently selected from C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl,—C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₆alkyl-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl,—C₁-C₆alkyl-(substituted or unsubstituted aryl),—C₁-C₆alkyl-(substituted or unsubstituted heteroaryl),—(CH₂)_(p)—CH(substituted or unsubstituted aryl)₂,—(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,—(CH₂)_(p)—CH(substituted or unsubstituted aryl)(substituted orunsubstituted heteroaryl), -(substituted or unsubstitutedaryl)-(substituted or unsubstituted aryl), -(substituted orunsubstituted aryl)-(substituted or unsubstituted heteroaryl),-(substituted or unsubstituted heteroaryl)-(substituted or unsubstitutedaryl), -(substituted or unsubstituted heteroaryl)-(substituted orunsubstituted heteroaryl); p is 0, 1 or 2; R^(8a) and R^(8b) areindependently selected from H, C₁-C₆alkyl, and C₁-C₆fluoroalkyl; R^(8c)and R^(8d) are independently selected from H, C₁-C₆alkyl, andC₁-C₆fluoroalkyl; where each substituted alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R⁹; andeach R⁹ is independently selected from halogen, —OH, —SH, (C═O), CN,C₁-C₄alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —NH₂,—NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH, —C(═O)NH₂,—C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,—NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;—O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, ortwo R⁹ together with the atoms to which they are attached form amethylene dioxy or ethylene dioxy ring substituted or unsubstituted withhalogen, —OH, or C₁-C₃alkyl.
 10. The compound of claim 9, orpharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, wherein: W² is C(R^(8c))(R^(8d)); R¹ is H; R^(2a), R^(2b) areindependently selected from H, and C₁-C₃alkyl;

is

R^(8a), R^(8b), R^(8c), R^(8d) are independently selected from H andC₁-C₃alkyl; R⁷ is selected from


11. The compound of claim 1, or pharmaceutically acceptable salt,N-oxide, racemate or stereoisomer thereof, wherein the compound has oneof the following structures:

or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof.
 12. A pharmaceutical composition comprising a compound of anyone of claim 1, or pharmaceutically acceptable salt, N-oxide, racemateor stereoisomer thereof, and a pharmaceutically acceptable carrier.